Diphenyl imidazoles as potassium channel modulators

ABSTRACT

Novel compounds of Formula 1 are useful to treat disorders responsive to openers of the large conductance calcium-activated potassium channels:                    
     wherein “Het” is one of a select group of heterocyclic moieties; Z is independently for each occurrence selected from O or S; R a , R b  and R c  each are independently selected from hydrogen, halogen, OH, CF 3 , NO 2 , or                    
     provided R c  is not hydrogen; and when R a  and R b  are hydrogen, R c  may be a heterocyclic moiety selected from the group consisting of imidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, and pyridin-2-yl; R d  and R e  each are independently selected from hydrogen, halogen, CF 3 , NO 2  or imidazol-1-yl; m, n and p each are independently selected from an integer of 0 or 1; and R f  and R g  each are independently hydrogen; C 1-4  alkyl; or R f  and R g , taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from the group consisting of N-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine and imidazolinone.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional application of co-pending application U.S. Ser. No.09/197,887, filed Nov. 23, 1998, which is a divisional of U.S. Ser. No.08/902,684, filed Jul. 30, 1997, now U.S. Pat. No. 5,869,509, whichclaims the benefit of provisional application U.S. Ser. No. 60/022,983,filed Jul. 31, 1996.

FIELD OF THE INVENTION

The present invention is directed to novel diphenyl heterocyclicderivatives which are modulators of the large-conductancecalcium-activated potassium (BK) channels and, therefore, useful in theprotection of neuronal cells, especially in the treatment or preventionof ischemic stroke. The present invention is also directed to a methodof treatment with the novel compounds and to pharmaceutical compositionscontaining them.

BACKGROUND OF THE INVENTION

Stroke is presently recognized as the third leading cause of adultdisability and death in the United States and Europe. In the pastdecade, several therapeutic approaches for the minimization ofstroke-related brain damage have been pursued including inhibitors ofAMPA/kainate, N-methyl-D-aspartate (NMDA) and adenosine reuptakeinhibitors. It is the object of the present invention to provide novelcompounds that will modulate potassium channels, in particular,large-conductance calcium-activated potassium (BK) channels which willbe useful in reducing neuronal damage during ischemic conditions of astroke episode.

Potassium channels play a key role in regulation of cell membranepotential and modulation of cell excitability. Potassium channels arethemselves regulated by voltage, cell metabolism, calcium ion andreceptor mediated processes. [Cook, N. S., Trends in Pharmacol. Sciences(1988), 9, p. 21-28; and Quast, U. and Cook, N. S., Trends in Pharmacol.Sciences (1989), 10, p. 431-435]. Calcium-activated potassium (K_(Ca))channels are a diverse group of ion channels that share a dependence onintracellular calcium ions for activity. The activity of K_(Ca) channelsis regulated by intracellular [Ca²⁺], membrane potential andphosphorylation. On the basis of their single-channel conductances insymmetrical K⁺ solutions, K_(Ca) channels are divided into threesubclasses: large conductance (BK)>150 pS; intermediate conductance50-150 pS; small conductance<50 pS. (“pS” stands for picosiemen, a unitof electrical conductance.) Large-conductance calcium-activatedpotassium (BK) channels are present in many excitable cells includingneurons, cardiac cells and various types of smooth muscle cells.[Singer, J. J. and Walsh, J. V., Pflügers Archiv. (1987) 408, p. 98-111;Baró, I., and Escande, D., Pflügers Archiv. (1989) 414 (Suppl. 1), p.S168-S170; and Ahmed, F. et al., Br. J. Pharmacol. (1984) 83, p.227-233].

Potassium ions play a dominant role in controlling the resting membranepotential in most excitable cells and in maintaining the transmembranevoltage near the K⁺ equilibrium potential (E_(k)) of about −90 mV. Ithas been shown that opening of potassium channels shifts the cellmembrane potential towards the equilibrium potassium membrane potential(E_(k)), resulting in hyperpolarization of the cell. [Cook, N. S.,Trends in Pharmacol. Sciences (1988), 9, p. 21-28]. Hyperpolarized cellsshow a reduced response to potentially damaging depolarizing stimuli. BKchannels which are regulated by both voltage and intracellular Ca²⁺ actto limit depolarization and calcium entry and may be particularlyeffective in blocking damaging stimuli. Therefore cell hyperpolarizationvia opening of BK channels may result in protection of neuronal cellsunder ischemic conditions.

The role of potassium channels in the operation of the smooth muscle ofthe human urinary bladder is discussed by S. Trivedi, et al. inBiochemical and Biophysical Research Communications, (1995), 213, No. 2,p. 404-409.

A range of synthetic and naturally occuring compounds with BK openingactivity have been reported. The avena pyrone extracted from avenasativa-common oats has been identified as a BK channel opener using alipid bi-layer technique [International Patent application WO 93/08800,published May 13, 1993]. 6-Bromo-8-(methylamino)imidazo[1,2-a]pyrazine-2-carbonitrile (SCA-40) has been described as aBK channel opener on the basis of limited electrophysiologicalexperiments [Laurent, F. et al., Br. J. Pharmacol. (1993) 108, p.622-626]. The flavanoid, Phloretin has been found to affect the openingof Ca²⁺-activated potassium channels in myelinated nerve fibers ofXenopus laevis using outside-out patches [Koh, D-S., et al.,Neuroscience Lett. (1994) 165, p.167-170].

EPO 0-435177-A2 published on Jul. 3, 1991, discloses substitutedtriazolones of Formula (i)

wherein

R and R₂ are C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, or trifluoromethyl and

(R₂)_(m) is methylenedioxy;

R₁ is hydrogen or C₁₋₄ alkyl; and

m and n are 0, 1 or 2.

These compounds are anticonvulsants. Note that, in Formula (i)compounds, R cannot be hydroxyl.

U.S. Pat. No. 5,331,002 issued to J. A. Miller on Jul. 19, 1994,discloses compounds of Formula ii:

wherein

R is halogen, trifluoromethyl, C₁₋₄ alkyl or C₁₋₄ alkoxy;

n=0, 1 or 2;

R₂ is hydrogen or C₁₋₃ alkyl; and

R₄ is C₁₋₃ alkyl.

These Formula ii compounds are memory enhancers. Note that the heterorings bear only one substituted phenyl moiety in structure ii.

U.S. Pat. No. 3,971,803 issued to S. Rosenberger and K. Schwarzenbach onJul. 27, 1976, relates to compounds of Formula iii:

wherein

R₁ is alkyl, cycloalkyl or aralkyl;

R₂ is hydrogen or R₁;

R₃ is hydrogen or C₁₋₄ alkyl;

Y and Z are independently O or S;

R₄ is either (1), if m=1, C₁₋₈ alkylene, —C_(x)H_(2x)—Q—C_(y)H_(2y)— (Qis O or S, x and y are integers whose sum is 2 to 4), phenylene,diphenylene or naphthalene or a

group;

or (2) if m=2, alkylene, alkylene ether, alkylene thioether,diphenylene, or napthalene. The compounds are antioxidants for organicpolymers.

EPO 0-533276-A1 published on Mar. 24, 1993, shows compounds of Formulaiv:

wherein one of P or Q is an ortho-substituted phenyl group and the othera substituted benzyl. The Formula iv compounds are miticides andinsecticides.

U.S. Pat. No. 5,116,858 issued to Y. Hayashi, et al. on May 26, 1992,discusses 4-imidazolone compounds which have activity as lipidperoxidase inhibitors. They may be of Formula v:

wherein X₄ is H, halogen, alkyl or alkoxy, p is 1 to 3, Y is

or ═C(OH)—, R₁ is (cyclo)alkyl, alkenyl, or aralkyl and R₂ and R₃ are Hor a variety of hydrocarbon, or hydrocarbonoxy groups.

A. E. Wilder Smith disclosed in Arzneim. Forsch. (1967) 67, No. 17, p.768-772, the preparation and study of compounds of Formula vi:

wherein X is H or Cl and n is 1 or 2. The compounds have tuberculostaticproperties. Formula vi compounds do not encompass substitution para tothe hydroxyl group.

U.S. Pat. No. 5,436,252 issued to S. M. Sorensen, et al., on Jul. 25,1995, describes the treatment of neurodegenerative disorders using5-aryl-3H-1,2,4-triazol-3-ones of Formula vii:

wherein Ar is individually phenyl, naphthyl or an aromatic heterocyclicgroup, R₁ is hydrogen or lower alkyl, R₂ is lower alkyl, R isindividually alkyl, alkoxy, hydroxy, halogen or trifluoromethyl, n is0-2 or (R)_(n)—Ar together is methylenedioxyphenyl. Formula vii does notencompass diphenyl compounds.

None of these discloses all of the compounds of the invention or theiruse as potassium channel modulators.

SUMMARY OF THE INVENTION

The present invention provides novel diphenyl heterocyclic derivativeshaving the general formula

wherein “Het” is a moiety selected from the group consisting of (A)through (H):

wherein Z is independently for each occurrence selected from O or S;R^(a), R^(b) and R^(c) each are independently selected from hydrogen,halogen, OH, CF₃, NO₂, or

provided R^(c) is not hydrogen; and when R^(a) and R^(b) are hydrogen,R^(c) may be a heterocyclic moiety selected from the group consisting ofimidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, andpyridin-2-yl; R^(d) and R^(e) each are independently selected fromhydrogen, halogen, CF₃, NO₂ or imidazol-1-yl; m, n and p each areindependently selected from an integer of 0 or 1; and R^(f) and R^(g)each are independently hydrogen; C₁₋₄ alkyl; or R^(f) and R^(g), takentogether with the nitrogen atom to which they are attached, is aheterocyclic moiety selected from the group consisting ofN-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine andimidazolinone.

Nontoxic pharmaceutically acceptable salts, solvates or hydrates ofFormula 1 compounds are also covered by this invention. The inventionprovides these compounds as well as compositions and methods whichemploy them.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel diphenyl heterocyclic derivativeswhich are potent openers of the high conductance, calcium-activatedK⁺-channels (BK channel) and which have Formula 1

wherein “Het” is a moiety selected from the group consisting of (A)through (H):

wherein Z is independently for each occurrence selected from O or S;R^(a), R^(b) and R^(c) each are independently selected from hydrogen,halogen, OH, CF₃, NO₂, or

provided R^(c) is not hydrogen; and when R^(a) and R^(b) are hydrogen,R^(c) may be a heterocyclic moiety selected from the group consisting ofimidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, andpyridin-2-yl; R^(d) and R^(e) each are independently selected fromhydrogen, halogen, CF₃, NO₂ or imidazol-1-yl; m, n and p each areindependently selected from an integer of 0 or 1; and R^(f) and R^(g)each are independently hydrogen; C₁₋₄ alkyl; or R^(f) and R^(g), takentogether with the nitrogen atom to which they are attached, is aheterocyclic moiety selected from the group consisting ofN-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine andimidazolinone.

The present invention also provides a method for the treatment of orprotection from disorders which are mediated by opening of the largeconductance calcium-activated K⁺ channels (BK channels) in a mammal inneed thereof, which comprises administering to said mammal atherapeutically effective amount of a compound of Formula 1 or anontoxic pharmaceutically acceptable salt thereof. Preferably, thecompounds of Formula 1 are useful in the treatment of ischemia,convulsions, asthma, irritable bowel syndrome, migraine, traumatic braininjury, male erectile dysfunction, and urinary incontinence and otherdisorders sensitive to BK channel activating activity.

The term “Z” as used herein and in the claims is independently selectedfrom O or S. It is to be understood that when Z is oxygen the O atom maybe part of an ether link (C—O—C) or a carbonyl (C═O) group; and when Zis sulfur, the S atom may be part of a thioether (C—S—C) or thiocarbonyl(C═S) moiety.

Optical isomers and other isomers of heterocyclic moieties (A) through(H) are useful, as are all isomers of Formula 1 compounds in general.Prodrugs and other forms can be employed.

The term “C₁₋₄ alkyl” as used herein and in the claims (unless thecontext indicates otherwise) means straight or branched chain alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, Preferably, these groups contain from 1 to 2 carbon atoms.Unless otherwise specified, the term “halogen” as used herein and in theclaims is intended to include bromine, chlorine, iodine and fluorinewhile the term “halide” is intended to include bromine, chloride andiodide anion.

The term “Het” as used herein and in the claims (unless the contextindicates otherwise) is intended to include all the heterocyclicmoieties defined by the Formulas (A) through (H) in which eachheterocyclic moiety is disubstituted and attached as indicated by thetwo bonds shown in the structural formulas. Furthermore, it is to beunderstood that the attachment of the phenyl groups can be either, forexample, 4,5- or 5,4-disubstituted; 3,5 or 5,3-disubstituted; 1,5 or5,1-disubstituted and other isomers of the “Het” moieties (A) through(H).

The term “nontoxic pharmaceutically acceptable salt” as used herein andin the claims is intended to include nontoxic acid and base additionsalts. Suitable acids include sulfuric, phosphoric, hydrochloric,hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, fumaric,mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic,and the like. Suitable inorganic bases, such as alkali and alkalineearth metal bases, include metallic cations such as sodium, potassium,magnesium, calcium and the like.

Generally, pharmaceutically acceptable salts of the invention are thosein which the counter-ion does not contribute significantly to thetoxicity or pharmacological activity of the salt. In some instances,they have physical properties which make them more desirable forpharmaceutical formulations, such as solubility, lack of hygroscopicity,compressibility with respect to tablet formation and compatibility withother ingredients with which the substance may be used forpharmaceutical purposes. The salts are routinely made by admixture of aFormula 1 compound with the selected acid or base, preferably by contactin solution employing an excess of commonly used inert solvents such aswater, ether, benzene, methanol, ethanol, ethyl acetate andacetonitrile. They may also be made by metathesis or treatment with anion exchange resin under conditions in which the appropriate ion of asalt of the substance of the Formula 1 is replaced by another ion underconditions which allow for separation of the desired species such as byprecipitation from solution or extraction into a solvent, or elutionfrom or retention on an ion exchange resin.

Certain compounds of the present invention can exist as solvated formsincluding hydrated forms such as monohydrate, dihydrate, hemihydrate,trihydrate, tetrahydrate and the like. The products may be truesolvates, while in other cases, the products may merely retainadventitious solvent or be a mixture of solvate plus some adventitioussolvent. It should be appreciated by those skilled in the art thatsolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention.

In the method of the present invention, the term “therapeuticallyeffective amount” means the total amount of each active component of thecomposition that is sufficient to show a meaningful patient benefit,i.e., healing of acute conditions characterized by openers of largeconductance calcium-activated K⁺ channels or increase in the rate ofhealing of such conditions. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously. Theterms “treat, treating, treatment” as used herein and in the claimsmeans preventing or ameliorating diseases, tissue damage and/or symptomsassociated with dysfunction of cellular membrane polarization andconductance.

The compounds of Formula 1 may be prepared by various procedures such asthose illustrated herein in the examples, in the Reaction Schemes andvariations thereof which would be evident to those skilled in the art.

1,2-Diarylheterocycles

The triazolones of type I and II were prepared as outlined in ReactionSchemes 1 and 2. For instance, phenylacetic acid or benzoic acids (wheren=0) were activated as their acid chlorides and coupled with an aniline.The resultant amides III and IV were treated with phosphoruspentachloride in benzene at reflux and intermediate iminoyl chloridestrapped with anhydrous hydrazine to give amidrazones V and VI,respectively. Cyclization of the amidrazones by treatment withcarbonyldiimidazole in THF gave the triazolone ring system.Demethylation was accomplished upon heating the triazolones at 225° C.in the presence of pyridine hydrochloride and the phenols I and II wereisolated in good overall yields (˜45-55%).

Reaction Schemes 3-5 depict the preparation of several relatedring-systems. The triazolothione VII was prepared from amidrazone V upontreatment with 1,1′-thiocarbonyldiimidazole in THF, followed bydemethylation with pyridinium hydrochloride (Reaction Scheme 3).Condensing the same amidrazone V with cyanogen bromide in the presenceof sodium bicarbonate lead to the amino triazole VIII afterdemethylation of the more sensitive amino triazole was performed withboron tribromide in cold (0° C.) methylene chloride.

Imidazoles, as illustrated in Reaction Scheme 4, were obtained when theintermediate iminoyl chlorides III and IV were trapped withaminoacetaldehyde diethyl acetal. Heating the acetals at reflux inbenzene under Dean-Stark conditions caused cyclization to the imidazolerings which underwent demethylation with pyridinium hydrochloride toafford systems IX and X. A third imidazole XI was prepared uponcondensation of an aniline with 5-chloro-2-methoxybenzaldehyde. Theintermediate imine was treated with tosylmethylisocyanide under basicconditions to generate imidazole IX after demethylation with BBr₃.

Addition of 2-aminoacetophenone to 5-chloro-2-methoxyisocyanate asoutlined in Reaction Scheme 5 gave a 2-oxophenethylurea XII which upondissolution in concentrated sulfuric acid at 0° C. cyclized, and afterdemethylation with boron tribromide, provided imidazolone XIII. Animidazolinedione derivative XIV was obtained upon condensation ofN-(5-chloro-2-methoxyphenyl)urea with phenylglyoxal followed bydemethylation upon exposure to boron tribromide.

1-Aryl-3-benzylheterocycles

The synthesis of 1-aryl-3-benzylheterocycles is described in ReactionSchemes 6 and 8-10. Oxadiazolones prepared according to literaturemethods were alkylated with benzyl bromides in the presence of potassiumcarbonate in acetonitrile at reflux. A second method, alkylation ofoxadiazolones with benzyl alcohols under Mitsunobu conditions, was alsoemployed to secure the same products. When Y=H. boron tribromidemediated demethylation gave product XV. For analogs wherein Y=NHAc, themethylether derivatives were hydrolyzed in 10% HCl/ethanol at reflux togive anilines, and demethylation gave products of structure XVI.

A further analog, chloro derivative XVII, was prepared upondemethylation and selective chlorination with sulfuryl chloride in thepresence of catalytic diisobutylamine prior to acetate hydrolysis.

X′=chloro, 2-pyridinyl, 1-imidazole, 1-methyl-2-imidazole, or4-morpholinylmethyl and Y=ethylmethylamino or hydrogen.

In several analogs (i.e., when X′=2-pyridinyl, 1-imidazole,1-methyl-2-imidazole, ethylmethylamino, or 4-morpholinylmethyl) theprecursor benzyl alcohols for the Mitsunobu reaction were notcommercially available. The preparation of these compounds isillustrated in Reaction Scheme 7.

Reaction Scheme 7

In all the compounds, the benzyl alcohols were prepared throughreduction of either an aldehyde or ester. The aryl rings werefunctionalized either through coupling methods or alkylation.

Reaction Scheme 8

Modifications to the aryl ring (i.e., when R₁=F, R₃=CF₃, and R₃=F,R₄=CF₃) were affected by ipso substitution of the fluorine withimidazole to give XVIII after demethylation with pyridine hydrochloride(Reaction Scheme 8).

In one example, the oxadiazolone ring system reacted smoothly withLawesson's reagent to give the thione analog XIX after demethylationwith boron tribromide.

Reaction Scheme 9 outlines the modification of an aniline to severalderivatives upon treatment with bromoacetyl bromide and subsequentalkylation (with Q_(N)=morpholine, thiomorpholine, N-methyl piperazine,N-phenyl piperazine, N-benzyl piperazine, dimethylamine) to give productXX after demethylation.

Altematively, conversion of the same aniline to an isocyanate, orisothiocyanate, and addition of aminoacetaldehyde diethyl acetal andcyclization afforded imidazolone (thione) XXI.

Triazolone products were prepared as outlined in Reaction Scheme 10.Alkylation of an ethoxy triazole in sodium hydride DMF gave productsXXII and a regioisomer (not shown) as a mixture (1:1). The products werepurified by silica gel chromatography and the ethoxy triazole subjectedto hydrolysis in 10% HCl/ethanol in order to afford the triazolone ringsystem. Hydrolysis of the acetate also occurred under these conditions(Y=NHAc), and demethylation with boron tribromide gave triazoloneproducts of Formula XXIII.

1,3-Diarylheterocycles

Alkylation of chloroxazone withα′-bromo-4-(trifluoromethyl)-acetophenone in sodium hydride/DMF gave thebenzoxazolone XXIV in good yield (Reaction Scheme 11). Further treatmentwith ammonium acetate at reflux in acetic acid caused rearrangement toimidazolone product XXV.

Oxadiazolone XXVI, illustrated in Reaction Scheme 12, wa s prepared uponacylation of a phenyldhydrazine with activated benzoic acids.Cyclization of the resultant hydrazide with carbonyidiimidazole gave theoxadiazolone ring system, and hydrolysis (as above when Y=NHAc) prior todemethylation with boron tribromide gave XXVI.

A series of triazolones was prepared as depicted in Reaction Scheme 13.Condensation of glyoxalic acids with phenylhydrazines in refluxingethanol gave carboxylic acids XXVII. Exposure to diphenylphosphorylazidegenerated isocyanates which were trapped intramolecularly to givetriazolones XXVIII after demethylation with boron tribromide. Theregioisomeric triazolone XXIX was prepared in a similar manner byreversing the substitution pattern of the hydrazine and glyoxalic acidstarting materials as shown in Reaction Scheme 14.

In one preferred embodiment of the invention, the compounds are ofFormula (1a) or Formula (1b)

wherein R^(a) through R^(e) are as defined above. In preferred compoundsof Formula (1a) or Formula (1b), R^(a) and R^(b) are H, OH, NH₂ or Cl;R^(c) is Cl; R^(d) and R^(e) are CF₃ or H; with m=0 and n=0 or 1.

In another preferred embodiment of the invention the compounds are ofFormula (1c)

wherein R^(a) through R^(e) are as defined above. In preferred Formula1c compounds, R^(a) and R^(b) are OH, H, NH₂ or Cl; R^(c) is Cl; R^(d)and R^(e) are H, CF₃or Cl; with m=0 or 1 and n=0.

In yet another preferred embodiment, the compounds of the inventionconform to Formula (1d) or Formula (1e)

wherein R^(a) and R^(b) are hydrogen, hydroxyl, chloro or NH₂; R^(c) ischloro; R^(d) and R^(e) are hydrogen, trifluoromethyl, fluoro or chloro.It is generally preferred that at least one of R^(d) and R^(e) betrifluoromethyl or chloro.

In still another preferred embodiment of the invention the compoundshave Formula (1f)

R^(a), R^(b) and R^(c) each are independently selected from hydrogen,halogen, OH, CF₃, NO₂, or

provided R^(c) is not hydrogen; and when R^(a) and R^(b) are hydrogen,R^(c) may be a heterocyclic moiety selected from the group consisting ofimidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, andpyridin-2-yl; R^(d) and R^(e) each are independently selected fromhydrogen, halogen, CF₃, NO₂ or imidazol-1-yl; m, n and p each areindependently selected from an integer of0 or 1; and R^(f) and R^(g)each are independently hydrogen; C₁₋₄ alkyl; or R^(f) and R^(g), takentogether with the nitrogen atom to which they are attached, is aheterocyclic moiety selected from the group consisting ofN-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine andimidazolinone.

In yet another preferred embodiment, the compounds of the inventionconform to Formula (1g)

wherein R^(a) and R^(b) are H, OH, Cl, or NH₂; R^(c) is chloro; R^(d)and R^(e) are H, CF₃ or Cl; with m=1. It is generally preferred that atleast one of R^(d) and R^(e) be CF₃ or Cl in the (1g) compounds.

In still another preferred embodiment, the compounds of the inventionconform to Formula (1h)

wherein R^(a) and R^(b) are hydrogen, hydroxyl, chloro or NH₂; R^(c) ischloro; R^(d) and R^(e) are hydrogen, trifluomethyl or chloro. It isgenerally preferred that at least one of R^(d) and R^(e) be CF₃ or Cl inthe Formula (1h) compounds.

Preferred compounds include:

4-(5-Chloro-2-hydroxyphenyl)-5-[3,5-bis(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-(5-Chloro-2-hydroxyphenyl)-5-[3-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-(5-Chloro-2-hydroxyphenyl)-5-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-[2-Hydroxy-5-(trifluoromethyl)phenyl]-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-4-3H-1,2,4-triazol-3-one;

4-(5-Chloro-2-hydroxyphenyl)-5-[[(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione;

4-Chloro-2-[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl]phenol;

5-(5-Chloro-2-hydroxyphenyl)-4-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

5-(5-Chloro-2-hydroxyphenyl)-4-[[4-(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-Chloro-2-[1-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]phenol;

4-Chloro-2-[1-phenyl-1H-imidazol-2-yl]phenol;

4-Chloro-2-[3-amino[5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-4-yl]]phenol;

1-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazole;

1-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-5-phenyl-2H-imidazol-2-one;

3-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[4-(Amino)-5-chloro-2-hydroxyphenyl]methyl]-5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[2-Hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[2-Hydroxy-5-chlorophenyl]methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-fluoro-3-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

3-[[2-Hydroxy-5-chlorophenyl]methyl]-5-[2-chloro-5-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[2-Hydroxy-5-chlorophenyl]methyl]-5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[2-fluoro-4-(trifluoromethyl)-phenyl]1,3,4-oxadiazol-2(3H)-one;

3-[(4-Amino-3,5-dichloro-2-hydroxyphenyl)methyl]-5-[3,4-dichlorophenyl]1,3,4-oxadiazol-2(3H)-one;

3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[2-(1H-imidazol-1-yl)-4-(trifluoro-methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(1H-imidazol-1-yl)-3-(trifluoro-methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[2-Hydroxy-5-(4-morpholinylmethyl)phenyl]methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[5-Chloro-4-[(ethylmethylamino)-2-hydroxyphenyl]methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazl-2(3H)-one;

3-[[2-Hydroxy-5-(2-pyridinyl)phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[5-(1-Methyl-1H-imidazol-2-yl)-2-hydroxyphenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[2-hydroxy-5-(1-methyl-1H-imidazo-2-yl)phenyl]methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[2-Hydroxy-5-(1H-imidazol-1-yl)phenyl]methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[2-Hydroxy-5-(1H-imidazol-1-yl)phenyl]methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

N-[2-Chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-1-yl]methyl]-5-hydroxyphenyl]-4-morpholineacetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-thiomorpholineacetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-methyl-1-piperazineacetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-phenyl-1-piperazineacetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-benzyl-1-piperazineacetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-2-(dimethylamino)acetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-(1,1′-Biphenyl)-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-methyl-1-piperazineacetamide;

N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[naphth-2-yl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-morpholineacetamide;

3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-thione;

3-[[5-Chloro-4-(2,3-dihydro-2-oxo-1H-imidazol-1-yl)-2-hydroxyphenyl]-methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

3-[[5-Chloro-4-(2,3-dihydro-2-thio-1H-imidazol-1-yl)-2-hydroxyphenyl]-methyl]-5-[4-(trifluoromethyl)phenyl-1,3,4-oxadiazol-2(3H)-one;

2-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one;

2-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[3,4-dichlorophenyl]-3H-1,2,4-triazol-3-one;

2-[(5-Chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)-phenyl]-3H-1,2,4-triazol-3-one;

5-(4-Amino-5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-(3H)-one;

5-(4-Amino-5-chloro-2-hydroxyphenyl)-3-phenyl-1,3,4-oxadiazole-2-(3H)-one;

5-(5-Chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one;

5-(4-Amino-5-chloro-2-hydroxyphenyl)-3-[3,4-dichlorophenyl]-1,3,4-oxadiazole-2-(3H)-one;

1-(5-Chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,2,4(4H)-triazol-5-one;

1-(5-Chloro-2-hydroxyphenyl)-3-[3-(trifluoromethyl)phenyl]-1,2,4(4H)-triazol-5-one;

1-(5-Chloro-2-hydroxyphenyl)-3-[2-(trifluoromethyl)phenyl]-1,2,4(4H)-triazol-5-one;

1-(5-Chloro-2-hydroxyphenyl)-3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4(4H)-triazol-5-one;

1-(5-Chloro-2-hydroxyphenyl)-3-[2,4-bis(trifluoromethyl)phenyl]-1,2,4(4H)-triazol-5-one;

1-(5-Chloro-2-hydroxyphenyl)-3-[3-chloro-4-(trifluoromethyl)phenyl]-1,2,4(4H)-triazol-5-one;and

5-[5-Chloro-2-hydroxyphenyl]-2,4-dihydro-2-[4-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one.

In another aspect, this invention provides a method for the treatment ofor protection from disorders which are mediated by opening of the largeconductance calcium-activated K⁺ channels (BK channels) in a mammal inneed thereof, which comprises administering to said mammal atherapeutically effective amount of a compound of Formula 1 or anontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.Preferably, the compounds of Formula 1 are useful in the treatment ofischemia, convulsions, asthma, irritable bowel syndrome, migraine,traumatic brain injury, male erectile dysfuntion, and urinaryincontinence and other disorders sensitive to BK channel activatingactivity. Most preferably, the compounds of Formula 1 are useful in thetreatment of cerebral ischemia.

In still another aspect, this invention provides pharmaceuticalcompositions comprising at least one compound of Formula 1 incombination with a pharmaceutical adjuvant, carrier or diluent.

Biological Activity

Potassium (K⁺) channels are structurally and functionally diversefamilies of K⁺-selective channel proteins which are ubiquitous in cells,indicating their central importance in regulating a number of key cellfunctions [Rudy, B., Neuroscience, 25:729-749 (1988)]. While widelydistributed as a class, K⁺ channels are differentially distributed asindividual members of this class or as families. [Gehlert, D. R., etal., Neuroscience, 52:191-205 (1993)]. In general, activation of K⁺channels in cells, and particularly in excitable cells such as neuronsand muscle cells, leads to hyperpolarization of the cell membrane, or inthe case of depolarized cells, to repolarization. In addition to actingas an endogenous membrane voltage clamp, K⁺ channels can respond toimportant cellular events such as changes in the intracellularconcentration of ATP or the intracellular concentration of calcium(Ca²⁺). The central role of K⁺ channels in regulating numerous cellfunctions makes them particularly important targets for therapeuticdevelopment. [Cook, N. S., Potassium channels: Structure,classification, function and therapeutic potential. Ellis Horwood,Chinchester (1990)]. One class of K⁺ channels, the large-conductanceCa²⁺-activated K⁺ channels (BK or BK channels), is regulated bytransmembrane voltage, intracellular Ca²⁺, and a variety of otherfactors such as the phosphorylation state of the channel protein.[Latorre, R., et al., Ann. Rev. Physiol., 51:385-399 (1989)]. The large,single channel-conductance (generally>150 pS) and high degree ofspecificity for K⁺ of BK channels indicates that small numbers ofchannels could profoundly affect membrane conductance and cellexcitability. Additionally, the increase in open probability withincreasing intracellular Ca²⁺ indicates involvement of BK channels inthe modulation of Ca²⁺-dependent phenomena such as secretion andmuscular contraction. [Asano, M., et al., J. Pharmacol. Exp. Ther.,267:1277-1285 (1993)].

Openers of BK exert their cellular effects by increasing the openprobability of these channels [McKay, M. C., et al., J. Neurophysiol.,71:1873-1882 (1994); and Olesen, S.-P., Exp. Opin. Invest. Drugs,3:1181-1188 (1994)]. This increase in the opening of individual BKchannels collectively results in the hyperpolarization of cellmembranes, particularly in depolarized cells, produced by significantincreases in whole-cell BK-mediated conductance.

The ability of compounds described in the present invention to open BKchannels and increase whole-cell outward (K⁺) BK-mediated currents wasassessed under voltage-clamp conditions by determining their ability toincrease cloned mammalian (mSlo or hSlo) BK—mediated outward currentheterologously expressed in Xenopus oocytes [Butler, A., et al.,Science, 261:221-224 (1993); and Dworetzky, S. I., et al., Mol. BrainRes., 27:189-193 (1994)]. The two BK constructs employed representnearly structurally identical homologous proteins, and have proven to bepharmacologically identical in our tests. To isolate BK current fromnative (background, non-BK) current, the specific and potent BKchannel-blocking toxin iberiotoxin (IBTX) [Galvez, A., et al., J. Biol.Chem, 265:11083-11090 (1990)] was employed at a supramaximalconcentration (50 nM). The relative contribution of BK channels currentto total outward current was determined by subtraction of the currentremaining in the presence of IBTX (non-BK current) from the currentprofiles obtained in all other experimental conditions (control, drug,and wash). It was determined that at the tested concentration thecompounds profiled did not effect non-BK native currents in the oocytes.All compounds were tested in at least 5 oocytes and are reported atconcentrations of either 1, 5 or 20 μM; the effect of the selectedcompounds of Formula 1 on BK current was expressed as the percent ofcontrol IBTX-sensitive current and is listed in Table I. Recordings wereaccomplished using standard two-electrode voltage clamp techniques[Stuhmer, W., et al., Methods in Enzymology, Vol. 207:319-339 (1992)];voltage-clamp protocols consisted of 500-750 ms duration stepdepolarizations from a holding potential of −60 mV to +140 mV in 20 mVsteps. The experimental media (modified Barth's solution) consisted of(in mM): NaCl (88), NaHCO3 (2.4), KCl (1.0), HEPES (10), MgSO4 (0.82),Ca(NO3)2 (0.33), CaCl2 (0.41); pH 7.5.

TABLE I Effect of Selected Compounds on BK Channels Example Increase inNo. BK Current‡ 25 ++ 78 +++ 79 +++ 82 ++** 99 ++ 101 ++ 118 ++ 119 +131 ++* 140 +++ 142 ++ 143 ++ 144 +++ ‡Unless otherwise noted,concentration of test compound = 20 μM; expressed as percent of increaseover BK current in controls; *Concentration = 2.5 μM **Concentration = 1μM + = 100-125% ++ = 125-175% +++ = >175%

To determine the ability of these compounds to reduce cell lossresulting from neuronal ischemia, a standard rodent model of permanentfocal ischemia, involving occlusion of the middle cerebral artery in thespontaneously hypertensive rat (MCAO model) was employed [Tamura, A., etal., Journal of Cerebral Blood Flow and Metabolism, Volume 1, 53-60,(1981)].

Selected compounds have been evaluated in the focal stroke modelinvolving permanent middle cerebral artery occlusion (MCAO) in thespontaneously hypertensive rat. This procedure results in a reliablylarge neocortical infarct volume that is measured by means of vital dyeexclusion in serial slices through the brain 24 hours after MCAO. In thepresent test, compounds were administered using an i.v. or i.p. route ofadministration at two hours after occlusion. For example, in this model,the compound of Example 82 significantly reduced the cortical infarctvolume by about 14% when administered intraparitoneally (10 mg/kg) as asingle bolus 2 hours after middle cerebral artery occlusion as comparedto vehicle-treated (2% DMSO, 98% PG) control.

The results of the above in vitro and in vivo tests demonstrate that thecompounds of the instant invention are potent openers of thelarge-conductance calcium-activated K⁺ channels (BK channels). Thus, thecompounds of the present invention are useful for the treatment of humandisorders arising from dysfunction of cellular membrane polarization andconductance and, preferably, are indicated for the treatment ofischemia, convulsions, asthma, irritable bowel syndrome, migraine,traumatic brain injury, male erectile dysfunction, and urinaryincontinence and other disorders sensitive to BK channel activatingactivity. Most preferably, the compounds of Formula 1 are useful in thetreatment of cerebral ischemia.

Therefore, the compounds of Formula 1 or pharmaceutical compositionsthereof are useful in the treatment, alleviation or elimination ofdisorders or other disorders associated with the BK channels. Suchdisorders include ischemia, convulsions, asthma, irritable bowelsyndrome, migraine, traumatic brain injury, male erectile dysfunction,and urinary incontinence and other disorders sensitive to potassiumchannel openers.

In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula 1 incombination with a pharmaceutical adjuvant, carrier or diluent.

In still another embodiment, this invention relates to a method oftreatment or prevention of disorders responsive to opening of potassiumchannels in a mammal in need thereof, which comprises administering tosaid mammal a therapeutically effective amount of a compound of Formula1 or a nontoxic pharmaceutically acceptable salt, solvate or hydratethereof.

In yet another embodiment, this invention relates to a method fortreating an ischemic condition in a mammal in need thereof, whichcomprises administering to said mammal a therapeutically effectiveamount of a compound of Formula 1 or a non-toxic pharmaceuticallyacceptable salt, solvate or hydrate thereof.

For therapeutic use, the pharmacologically active compounds of Formula 1will normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inassociation with a solid or liquid pharmaceutically acceptable carrierand, optionally, with pharmaceutically acceptable adjuvants andexcipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral,parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, placed in a hard gelatincapsule in powder or pellet form, or in the form of a troche or lozenge.The solid carrier may contain conventional excipients such as bindingagents, fillers, tableting lubricants, disintegrants, wetting agents andthe like. The tablet may, if desired, be film coated by conventionaltechniques. If a liquid carrier is employed, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule, sterile vehicle forinjection, an aqueous or non-aqueous liquid suspension, or may be a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Liquid preparations may contain conventional additives such assuspending agents, emulsifying agents, wetting agents, non-aqueousvehicle (including edible oils), preservatives, as well as flavoringand/or coloring agents. For parenteral administration, a vehiclenormally will comprise sterile water, at least in large part, althoughsaline solutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Particularlyuseful is the administration of a compound of Formula 1 directly inparenteral formulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula 1 according to the invention. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

The dosage of the compounds of Formula 1 to achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of potassiumchannel activating activity desired and the potency of the particularcompound being utilized for the particular disorder of diseaseconcerned. It is also contemplated that the treatment and dosage of theparticular compound may be administered in unit dosage form and that theunit dosage form would be adjusted accordingly by one skilled in the artto reflect the relative level of activity. The decision as to theparticular dosage to be employed (and the number of times to beadministered per day) is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula 1 or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition as described herein is an amount of active ingredientfrom about 0.1 μg/kg to 100 mg/kg body weight. For parenteraladministration, the dose may be in the range of 1 μg/kg to 100 mg/kgbody weight for intravenous administration. The active ingredient willpreferably be administered either continuously or in equal doses fromone to four times a day. However, usually a small dosage isadministered, and the dosage is gradually increased until the optimaldosage for the host under treatment is determined.

However, it will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechoice of compound of be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way inasmuch as manyvariations of the invention are possible within the spirit of theinvention.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In the following examples, all temperatures are given in degreesCentigrade. Melting points were recorded on a Gallenkamp capillarymelting point apparatus temperatures are uncorrected. Proton magneticresonance (¹H NMR) was recorded on a Bruker AC 300. All spectra weredetermined in the solvents indicated and chemical shifts are reported inδ units downfield from the internal standard tetramethylsilane (TMS) andinterproton coupling constants are reported in Hertz (Hz). Splittingpatterns are designated as follows: s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad peak; dd, doublet of doublet; bd,broad doublet; dt, doublet of triplet; bs, broad singlet; dq, doublet ofquartet. Infrared (IR) spectra using potassium bromide (KBr) weredetermined on a Perkin Elmer 781 spectrometer from 4000 cm⁻¹ to 400cm⁻¹, calibrated to 1601 cm⁻¹ absorption of a polystyrene film andreported in reciprocal centimeters (cm⁻¹). Low resolution mass spectra(MS) and the apparent molecular (MH⁺) or (M-H)⁻ was determined on aFinnigen TSQ 7000. High resolution mass spectra was determined on aKratos MS50 in FAB mode using cesium iodide/glycerol as internalreference. The element analysis are reported as percent by weight.

The following preparations illustrate procedures for the preparation ofintermediates and methods for the preparation of products according tothis invention. It should also be evident to those skilled in the artthat appropriate substitution of both the materials and methodsdisclosed herein will produce the examples illustrated below and thoseencompassed by the scope of this invention.

Preparation No. 1

EXAMPLES 1-6

EXAMPLE 1 N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)benzamide

(III¹: X=Cl, n=0, R₁=R₃=CF₃, R₂=H)

5-Chloroansidine (5.6 g, 36.3 mmol) was dissolved in THF (350 mL) andsolution of 3,5-bis(trifluoromethyl)benzoyl chloride (10.1 g, 36.6mmol), dissolved in THF (85 ml), was added dropwise under N₂ at 0° C.followed by addition of triethylamine (5.3 mL, 1.7 mmol) . The solutionwas stirred 18 h at 24° C. and filtered to remove Et₃N.HCl.Concentration by rotary evaporation removed the solvent and gave a whitesolid 13.08 g (90%). Recrystallized from ethanol/water (2:1) gavecolorless needles mp 151-153° C.; IR(KBr, υ=cm⁻¹) 3298, 1654, 1534,1292, 1276, 1188, 1136, 804; ¹H NMR (300 MHz, DMSO-d₆) δ 3.83 (3H, s),7.13 (1H, d, J=8.9 Hz), 7.26 (1 H, dd, J=8.8 Hz, 2.7 Hz), 7.76 (1 H, d,J=2.6 Hz), 8.33 (1H, br.s), 8.56 (2H, br.s), 10.25 (1H, br.s);MS(DCl)m/z: 398(MH⁺). Anal. calcd. for C₁₆H₁₀ClF₆NO₂: C,48.32; H, 2.54;N, 3.52. Found: C, 48.35; H, 2.57; N, 3.49.

The following amides were prepared in a similar manner to Example 1.

EXAMPLE 2 N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzamide

(III²: X=Cl, n=0, R₁=R₃=H, R₂=CF₃)

mp 113-115° C.; Anal. calcd. for C₁₅H₁₁ClF₃NO₂.0.1 H₂O: C, 54.34; H,3.41; N, 4.23. Found: C, 54.37; H, 3.34; N, 4.18.

EXAMPLE 3 N-(5-Chloro-2-methoxyphenyl)-3-(trifluoromethyl)benzamide

(III³: X=Cl, n=0, R₁=CF₃, R₂=R₃=H)

mp 111-112.5° C.; Anal. calcd. for C₁₅H₁₁ClF₃NO₂: C, 54.65; H, 3.36; N,4.25. Found: C, 54.62; H, 3.33; N, 4.19.

EXAMPLE 4 N-(5-Chloro-2-methoxyphenyl)-4-fluorobenzamide

(III⁴: X=Cl, n=0, R₁=R₃=H, R₂=F)

mp 131.5-134° C.; Anal. calcd. for C₁₄H₁₁ClFNO₂.0.05 H₂O: C, 59.93; H,3.99; N, 4.99. Found: C, 59.86; H, 3.97; N, 4.97.

EXAMPLE 5N-(2-Methoxy-5-trifluoromethylphenyl)-4-trifluoromethyl-benzamide

(III⁵: X=CF₃, n=0, R₁=R₃=H, R₂=CF₃)

mp 132-133° C.; Anal. calcd. for C₁₆H₁₁F₆NO₂: C, 52.90; H, 3.05; N,3.86. Found: C, 52.78; H, 3.04; N, 3.87.

EXAMPLE 6N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzeneacetamide

(III⁶: X=Cl, n=1, R₁=R₃=H, R₂=CF₃)

mp 115-116° C.; Anal. calcd. for C₁₆H₁₃ClF₃NO₂.0.1 H₂O: C, 55.63; H,3.85; N, 4.06. Found: C, 55.86; H, 3.72; N, 3.98.

EXAMPLES 7 AND 8

EXAMPLE 7 5-Chloro-2-methoxy-N-[4-(trifluoromethyl)phenyl]benzamide

(IV⁷: n=0)

mp 131.5-132.5° C.; Anal. calcd. for C₁₅H₁₁ClF₃NO₂.0.01 H₂O: C, 54.62;H, 3.37; N, 4.25. Found: C, 54.61; H, 3.33; N, 4.18.

EXAMPLE 85-Chloro-2-methoxy-N-[4-(trifluoromethyl)phenyl]benzeneacetamide

(IV⁸: n=1)

mp 112-113° C.; Anal. calcd. for C₁₆H₁₃ClF₃NO₂: C, 55.91; H, 3.81; N,4.07. Found: C, 55.97; H, 3.78; N, 4.07.

EXAMPLES 9 AND 10

EXAMPLE 9 N-(5-chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)benzenecarbohydrazonamide

(V⁹: X=Cl, n=0, R₁=R₃=CF₃, R₂=H)

N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl) benzamide (8 g,20.1 mmol) was dissolved in benzene (100 ml) under N₂ and phosphorouspentachloride (4.6 g, 22.1 mmol) added. The solution was heated atreflux for 3 h and solvent removed by rotary evaporation. The residuewas taken up in THF (165 ml) and cannulated dropwise into a solution ofanhydrous hydrazine (6.4 ml) in the same solvent (165 ml) at 0° C. underN₂. After being stirred 1 h at 24° C., the reaction mixture was pouredinto water (200 ml) and extracted with ethyl acetate (2×250 ml) and theorganic phase washed with brine and dried over sodium sulfate.Concentration gave 7.69 g (93%) mp 117-120° C.; IR(KBr, υ=cm⁻¹) 3339,3252, 1591, 1510, 1384, 1284, 1255, 1182, 1128; ¹H NMR (300 MHz, CDCl₃)δ 3.93 (3H, s), 5.66 (2H, br.s), 5.94 (1H, br.s), 6.25-6.26 (1H, m),6.77-6.84 (2H, m), 7.78 (1H, s), 8.01 (2H, s); MS(DCl)m/z: 412(MH⁺).Anal. calcd. for C₁₆H₁₂ClF₆N₃O: C, 46.68; H, 2.94; N, 10.21. Found: C,46.77; H, 2.83; N, 9.95.

EXAMPLE 10 N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzenecarbohydrazonamide

(VI¹⁰: X=Cl, n=0, R₁=R₃=H, R₂=CF₃)

The title amidrazone was prepared in a similar manner to example 9.

mp 94-95° C.; H. Res. MS calcd. for C₁₅H₁₃ClF₃N₃O: 344.0777; Found:344.077; Dev: 2.2 ppm.

EXAMPLES 11-16

EXAMPLE 11 4-(5-Chloro-2-methoxyphenyl)-5-[3,5-bis(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I¹¹: X=Cl, n=0, R₁=R₃=CF₃, R₂=H)

N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl) benzenecarbohydrazonamide (4 g, 9.7 mmol) was taken up in THF (600 ml) under N₂and 1,1′-carbonyidiimidazole (1.9 g, 11.72 mmol) added. The solution wasstirred for 18 h at 24° C. before solvent was removed by rotaryevaporation. The residue was taken up in ethyl acetate (400 ml) andwashed with 0.1N HCl solution (100 ml), water (100 ml) and brine priorto drying over MgSO₄. Recrystallization from acetonitrile gave 2.92 g(68.6%) mp 205.5-207° C. IR(KBr, υ=cm⁻¹) 3170, 3057, 1726, 1504, 1277,1128; ¹H NMR (300 MHz, DMSO-d₆) δ 3.48 (3H, s), 7.15 (1H, d, J=9.0 Hz),7.55 (1H, dd, J=8.9 Hz, 2.6 Hz), 7.69 (1H, d, J=2.6 Hz), 7.87 (2H,br.s), 8.17 (1H, br.s), 12.50 (1H, br.s); MS(DCl)m/z: 438(MH⁺). Anal.calcd. for C₁₇H₁₀ClF₆N₃O₂: C, 46.65; H, 2.30; N, 9.60. Found: C, 46.71;H, 2.20; N, 9.60.

The triazolones of Examples 12 through 18 were prepared using aprocedure similar to Example 11.

EXAMPLE 124-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I¹²: X=Cl, n=0, R₁=R₃=H, R₂=CF₃)

mp 250-253° C.; Anal. calcd. for C₁₅H₁₁ClF₃N₃O₂.0.03 H₂O: C, 51.91; H,3.01; N, 11.35. Found: C, 52.11; H, 2.97; N, 11.32.

EXAMPLE 134-(5-Chloro-2-methoxyphenyl)-5-[3-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I¹³: X=Cl, n=0, R₁=CF₃, R₂=R₃=H)

mp 207.5-209° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂: C, 51.98; H, 3.00; N,11.37. Found: C, 52.12; H, 2.84; N, 11.51.

EXAMPLE 144-(5-Chloro-2-methoxyphenyl-5-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

(I¹⁴: X=Cl, n=0, R₁=R₃=H, R₂=F)

mp 270.5-273° C.; Anal. calcd. for C₁₅H₁₁ClFN₃O₂.0.02 H₂O: C, 56.30; H,3.48; N, 13.13. Found: C, 56.25; H, 3.39; N, 13.08.

EXAMPLE 154-[2-Methoxy-5-(trifluoromethyl)phenyl]-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I¹⁵: X=CF₃, n=0, R₁=R₃=H, R₂=CF₃)

mp 255-256° C.; Anal. calcd. for C₁₇H₁₁F₆N₃O₂: C, 50.63; H, 2.75; N,10.42. Found: C, 50.61; H, 2.66; N, 10.45.

EXAMPLE 164-(5-Chloro-2-methoxyphenyl)-[[-5,4-(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I¹⁶: X=Cl, n=1, R₁=R₃=H, R₂=CF₃)

mp 154-155° C.; Anal. calcd. for C₁₇H₁₃ClF₃N₃O₂: C, 53.21; H, 3.41; N,10.95. Found: C, 53.10; H, 3.46; N, 10.89.

EXAMPLES 17 AND 18

EXAMPLE 175-(5-Chloro-2-methoxyphenyl)-4-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(II¹⁷: n=0)

mp 213-214.5° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂: C, 51.19; H, 3.02; N,11.35. Found: C, 51.84; H, 2.95; N, 11.28.

EXAMPLE 185-(5-Chloro-2-methoxyphenyl)4-[[4-(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(II¹⁸: n=1)

mp 134-136° C.; Anal. calcd. for C₁₇H₁₃ClF₃N₃O₂.0.1 H₂O: C, 52.94; H,3.45; N, 10.89. Found: C, 52.94; H, 3.22; N, 10.95.

EXAMPLE 194-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione

(VII¹⁹)

N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzenecarbohydrazonamide (2.5 g, 7.27 mmol) was dissolved in THF (450 ml)under N₂ and 1,1′-thiocarbonyldiimidazole (1.95 g, 11.0 mmol) added. Thesolution was stirred at reflux for 18 h and solvent removed by rotaryevaporation. The residue was taken up in ethyl acetate (400 ml) andwashed with 0.1N HCl solution (100 ml), water (100 ml) and brine priorto drying over MgSO₄. Recrystallization from acetonitrile gave 1.91 g(68%) mp 275-280° C.; IR(KBr, υ=cm⁻¹) 3080, 3058, 3020, 2916, 1506,1488, 1322, 1288, 1174, 1130, 1110; ¹H NMR (300 MHz, DMSO-d₆) δ 3.51(3H, s), 7.17 (1H, d, J=9.0 Hz), 7.53-7.57 (3H, m), 7.69 (1H, d, J=2.6Hz), 7.77 (2H, d, J=8.4 Hz.s), 14.29 (1H, s); MS(DCl)m/z: 386(MH⁺).Anal. calcd. for C₁₆H₁₁ClF₃N₃OS.0.06 CH₃CN: C, 49.87; H, 2.90; N, 11.04.Found: C, 50.03; H, 2.94; N, 11.07.

EXAMPLE 204-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-amine

(VIII²⁰)

N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzenecarbohydrazonamide (1.5 g, 4.36 mmol) was dissolved in 1,4-dioxane (7ml) and cyanogen bromide (475 mg, 4.48 mmol) was added. A solution ofsodium bicarbonate (380 mg in 7 ml of water) was added dropise at roomtemperature and the reaction mixture was stirred for 3 h. An additional7 ml of water was added to the heterogenous reaction mixture beforefiltration and rinse with water. Recrystallization from acetonitrilegave 922 mg (57.3%) mp 247-248° C.; IR(KBr, υ=cm⁻¹) 3416, 3076, 3052,1652, 1561, 1504, 1322, 1110; ¹ H NMR (300 MHz, DMSO-d₆) δ 3.60 (3H, s),5.92 (2H, s), 7.22 (1H, d, J=9.5 Hz), 7.47 (2H, d, 8.3 Hz), 7.54-7.57(2H, m), 7.67 (1H, d, J=8.4 Hz).; MS(DCl)m/z: 369(MH⁺). Anal. calcd. forC₁₆H₁₂ClF₃N₄O: C, 52.12; H, 3.28; N, 15.19. Found: C, 52.19; H, 3.20; N,15.29.

EXAMPLE 211-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazole

(XI²¹)

5-Chloroansidine (6.0 g, 38.2 mmol) and 4-ααα-trifluoro-tolualdehyde(6.6 g, 38.2 mmol) were dissolved in methanol (250 ml) and stirred for 3h. The solvent was removed by evaporation and the residue taken upbenzene (200 ml) and the solution heated under Dean-Stark conditions toremove traces of methanol prior to distillation of the benzene. Theresidue was taken up in DMF and tosylmethylisocyanide (7.46 g, 3.82mmol) and DBU (0.5 ml, 3.82 mmol) were added under N₂. The reactionmixture was stirred at 24° C. for 48 h before being diluted with water(1 vol) and extracted with ethyl acetate. The organic phase was washedwith water, brine, and dried. Chromatograhpy, elution with 30% ethylacetate/benzene, gave 1 g (8%) mp 158-159° C.; IR(KBr, υ=cm⁻¹) 1504,1462, 1324, 1260, 1176, 1122; ¹H NMR (300 MHz, CDCl₃) δ 3.49 (3H, s),6.86 (1H, d, J=8.9 Hz), 7.20-7.24 (3H, m), 7.32-7.38 (2H, m), 7.48 (2H,d, J=8.2 Hz), 7.60 (1H, s); MS(DCl)m/z: 353(MH⁺). Anal. calcd. forC₁₇H₁₂ClF₃N₂O: C, 57.88; H, 3.43; N, 7.94. Found: C, 58.08; H, 3.50; N,7.91.

EXAMPLE 221-(5-Chloro-2-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazole

(IX²²)

N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzamide (5.17 g, 15.7mmol) was dissolved in benzene (100 ml) under N₂ and phosphorouspentachloride (3.61 g, 17.3 mmol) added. The solution was heated atreflux for 2.5 h before distillation in vacuo to remove solvent andphosphorosoxychloride. The residue was taken up in THF (55 ml) andcannulated dropwise into a solution of aminoacetaldehyde diethyl acetal(5 ml, 34.4 mmol) in 50 ml of the same solvent at 0° C. under N₂. Afterbeing stirred 18 h at 24° C., the reaction mixture was diluted withdiethylether (1.5 vol) and filtered. The filtrate was concentrated byrotary evaporation to give an oil (7.63 g) which was dissolved inbenzene (500 ml). Two equivalents of p-TsOH.H₂O (6 g, 30 mmol) was addedand the solution heated at reflux for 2 h under Dean-Stark conditions.The solution was concentrated by rotary evaporation and the residue waspartitioned between ethyl acetate and water. The aqueous phase wasextrated with ethyl acetate and the combined organic layers were washedwith water and brine before drying over MgSO₄. Chromatography on SiO₂,elution with 10% ethyl acetate/methylene chloride gave a solid 4.15 g(75%). mp 151-152.5° C.; IR(KBr, υ=cm⁻¹) 1504, 1464, 1324, 1284, 1246,1176, 1122, 1108, 1074,846; ¹H NMR (300 MHz, DMSO-d₆) δ 3.48 (3H, s),7.17-7.21 (2H, m), 7.43 (1H, d, J=1.3 Hz), 7.51-7.59 (4H, m), 7.66 (2H,d, J=8.4 Hz); MS(DCl)m/z: 353(MH⁺). Anal. calcd. for C₁₇H₁₂ClF₃N₂O: C,57.89; H, 3.43; N, 7.94. Found: C, 57.74; H, 3.40; N, 7.88.

The imidazoles of Examples 23 and 24 were prepared in a manner similarto that of Example 22.

EXAMPLES 23 AND 24

EXAMPLE 232-(5-Chloro-2-methoxyphenyl)-1-[4-(trifluoromethyl)phenyl]-1H-imidazole

(X²³: X=CF₃)

mp 95-106° C.; Anal. calcd. for C₁₇H₁₂ClF₃N₂O: C, 57.89; H, 3.43; N,7.94. Found: C, 58.20; H, 3.56; N, 7.87.

EXAMPLE 24 2-(5-Chloro-2-methoxyphenyl)-1-phenyl-1H-imidazole

(X²⁴: X=H)

mp 97-102° C.; Anal. calcd. for C₁₆H₁₃ClN₂O.0.06 H₂O: C, 67.24; H, 4.63;N, 9.80. Found: C, 67.02; H, 4.56; N, 9.72.

EXAMPLES 25-30

EXAMPLE 254-(5-Chloro-2-hydroxyphenyl)-5-[3,5-bis(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I²⁵: X=Cl, n=0, R₁=R₃=CF₃, R2=H)

5-[3,5-Bis(trifluoromethyl)phenyl]-4-(5-chloro-2-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.6 g, 3.6 mmol) was admixedwith pyridine hydrochloride (6.7 g, 58 mmol) and heated at 225° C. for 1h. After being cooled, the solid was covered with ethyl acetate (25 ml)and water (15 ml) and subjected to ultrasonication (bath) for severalminutes in order to break the solid free from the glass wall. Theorganic suspension was diluted with ethyl acetate (100 ml) washed withwater (25 ml), saturated sodium carbonate solution (25 ml), and brine.Concentration gave a solid 1.46 g (95%) which was recrystallized fromacetonitrile. mp 275-278° C. IR(KBr, υ=cm⁻¹) 3166, 1681, 1314, 1275,1180, 1140; ¹H NMR (300 MHz, DMSO₆) δ 6.92 (1H, d, J=8.8 Hz), 7.38 (1H,dd, J=8.8 Hz, 2.6 Hz), 7.58 (1H, d, J=2 Hz), 7.91 (2H, s), 8.17 (1H, s),10.45 (1H, s), 10.45 (1H, s), 12,44 (1H, s); MS(DCl)m/z: 424(MH⁺). Anal.calcd. for C₁₆H₈ClF₆N₃O₂: C, 45.36; H, 1.90; N, 9.92. Found: C, 45.28;H, 1.89; N, 9.77.

The phenols of Examples 26 through 36 were prepared in a manner similarto Example 25.

EXAMPLE 264-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I²⁶: X=Cl, n=0, R₁=R₃=H, R₂=CF₃)

mp 292-294° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₂: C, 50.68; H, 2.60; N,11.73. Found: C, 51.04; H, 2.74; N, 11.55.

EXAMPLE 274-(5-Chloro-2-hydroxyphenyl)-5-[3-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I²⁷: X=Cl, n=0, R₁=CF₃, R₂=R₃=H)

mp 232.5-233.5° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₂.0.05 EtOAc: C, 50.70;H, 2.63; N, 11.67. Found: C, 50.62; H, 2.56; N, 11.64.

EXAMPLE 284-(5-Chloro-2-hydroxyphenyl)-5-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

(I²⁸: X=Cl, n=0, R₁=R₃=H, R₂=F)

mp 270.5-272.5° C.; Anal. calcd. for C₁₄H₉ClFN₃O₂.0.075 H₂O: C, 54.77;H, 3.00; N, 13.69. Found: C, 54.77; H, 3.04; N, 13.71.

EXAMPLE 29[4,2-Hydroxy-5-(trifluoromethyl)phenyl]-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I²⁹: X=CF₃, n=0, R₁=R₃=H, R₂=CF₃)

mp 270-274° C.; Anal. calcd. for C₁₆H₉F₆N₃O₂: C, 48.88; H, 2,42; N,10.69. Found: C, 49.36; H, 2.24; N, 10.82.

EXAMPLE 304-(5-Chloro-2-hydroxyphenyl)-5-[[(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(I³⁰: X=Cl, n=1, R₁=R₃=H, R₂=CF₃)

mp 270-274° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂: C, 51.98; H, 3.00; N,11.37. Found: C, 51.92; H, 2.88; N, 11.23.

EXAMPLE 314-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione

(VII³¹)

mp 274-276° C.; H. Res. MS calcd. for: C₁₅H₉ClF₃N₃OS: 372.0185; Found:372.0197; Dev: 3.2 ppm.

EXAMPLE 324-Chloro-2-[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl]phenol

(IX³²)

mp 252-254° C.;

Anal. calcd. for C₁₆H₁₀ClF₃N₂O: C, 56.74; H, 2.98; N, 8.27. Found: C,56.65; H, 2.94; N, 8.14.

EXAMPLES 33 AND 34

EXAMPLE 335-(5-Chloro-2-hydroxyphenyl)-4-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(II³³: n=0)

mp 236-238.5° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₂.0.1 EtOAc: C, 50.75; H,2.71; N, 11.53. Found: C, 50.97; H, 2.81; N, 11.32.

EXAMPLE 345-(5-Chloro-2-hydroxyphenyl)-4-[[4-(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

(II³⁴: n=1)

mp 217-219° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂.0.1 H₂O: C, 51.72; H,3.04; N, 11.31. Found: C, 51.95; H, 2.90; N, 11.31.

EXAMPLES 35 AND 36

EXAMPLE 354-Chloro-2-[1-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]phenol

(X³⁵: X=CF₃)

mp 110-112.5° C.; Anal. calcd. for C₁₆H₁₀ClF₃N₂O.0.01 H₂O: C, 56.52; H,3.01; N, 8.24. Found: C, 56.68; H, 2.86; N, 8.18.

EXAMPLE 36 4-Chloro-2-[1-phenyl-1H-imidazol-2-yl]phenol

(X³⁶: X=H)

mp 137-138.5° C.; Anal. calcd. for C₁₅H₁₁ClN₂O: C, 66.55; H, 4.10; N,10.35. Found: C, 66.76; H, 4.24; N, 10.26.

EXAMPLE 374-Chloro-2-[3-amino-[5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-4-yl]]phenol

(VIII³⁷)

4-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)-phenyl]-4H-1,2,4-triazol-3-amine(1.5 g, 4.1 mmol) was taken up in methylene chloride (forms suspension),cooled to 0° C. under N₂, and from 3 to 6 eq. boron tribromide (25 ml,1.0M in CH₂Cl₂) added. The reaction was stirred at 24° C. for 18 h, and1N sodium hydroxide (80 ml) was added and the solvent was removed byrotary evaporation and the residue was taken up in ethyl acetate andenough THF added to complete dissolution. After being washed with 0.1NHCl solution and brine the solution was dried over MgSO4.Chromatography, elution 1% AcOH/5% methanol in dichloromethane gave 795mg (55%). mp 147-155° C. H. Res. MS calcd. for C₁₅H₁₀ClF₃N₄O: 355.0574;Found: 355.0566; Dev: 2.3 ppm.

EXAMPLE 381-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazole

(XI³⁸)

The title phenol was prepared by the BBr₃ method of Example 37.

mp 220-225° C.; Anal. calcd. for C₁₆H₁₀ClF₃N₂O.0.15 H₂O: C, 56.06; H,2.94; N, 8.17. Found: C, 55.65; H, 2.94; N, 7.81.

Preparation No. 2

EXAMPLE 39 N-(5-Chloro-2-methoxyphenyl)-N′-(2-oxo-2-phenylethyl)urea

(XII³⁹)

5-Chloro-2-methoxyphenylisocyanate (5.3 g, 29 mmol) was dissolved in THF(250 ml) under N₂ and heated to 60° C. To this solution was added2-aminoacetophenone-HCl (5 g, 29 mmol) followed by triethylamine (3.8 g,30 mmol). After being stirred 1.5 h, the reaction mixture was dilutedwith ethyl acetate (2 vol) and washed with 1N HCl solution, saturatedNaCO₃ solution, and brine before being dried, MgSO₄. Concentration gavea solid which was washed with diethylether 6 g (65%). mp 171-173° C.;IR(KBr, υ=cm⁻¹) 3336, 1706, 1644, 1600, 1560, 1482, 1262, 1220, 1182,1126; ¹H NMR (300 MHz, CDCl₃) δ 3.79 (3H, s), 4.84 (2H, d, J=4.3 Hz),5.97 (1H, br.s), 6.71 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.7 Hz, 2.5Hz), 7.97-8.00 (2H, m), 8.18 (1H, d, J=2.5 Hz); MS(DCl)m/z: 319(MH⁺);Anal. calcd. for C₁₆H₁₅ClN₂O₃: C, 60.29; H, 4.74; N, 8.79. Found: C,60.17; H, 4.64; N, 8.70.

EXAMPLE 40 1-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-one

(XIII⁴⁰)

N-(5-Chloro-2-methoxyphenyl)-N′-(2-oxo-2-phenylethyl) urea (4 g, 12.7mmol) was added to cold (0° C.) concentrated sulfuric acid and stirredfor 3 h. The reaction mixture was poured into ice water (2 vol), andextracted with ethyl acetate, washed with saturated NaHCO₃ solution andbrine before drying over MgSO₄. Recrystallization fromdiethylether/acetonitrile gave 1.35 g (36%). mp 133-134° C.; IR(KBr,υ=cm⁻¹) 2962, 1628, 1576, 1236, 1144, 1130; ¹H NMR (300 MHz, CDCl₃) δ3.90 (3H, s), 6.77 (1H, d, J=8.6 Hz), 6.91 (1H, dd, J=8.6 Hz, 2.5 Hz),7.16 (1H, s), 7.22-7.27 (1H, m), 7.35-7.40 (2H, m), 7.51-7.55 (3H, m),8.29 (1H, d, J=2.5 Hz); MS(DCl)m/z: 301 (MH⁺); Anal. calcd. forC₁₆H₁₃ClN₂O₂: C, 63.90; H, 4.36; N, 9.31. Found: C, 63.66; H, 4.30; N,9.21.

EXAMPLE 411-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-5-phenyl-2H-imidazol-2-one

(XIII⁴¹)

The title phenol was prepared according to the BBr₃ method of Example 37above.

mp 190-192° C.; Anal. calcd. for C₁₅H₁₁ClN₂O₂: C, 62.83; H, 3.87; N,9.77. Found: C, 62.87; H, 3.92; N, 9.82.

Preparation No. 3

EXAMPLE 42 1-(5-Chloro-2-methoxyphenyl)-5-phenyl-2,4-imidazolidinedione

(XIV⁴²)

N-(5-Chloro-2-methoxyphenyl)urea (1 g, 5 mmol) and phenylglyoxalmonohydrate (760 mg, 5 mmol) were taken up in absolute ethanol (100 ml)and acetic acid (1 ml) and 1 ml of conc. HCl added. The reaction mixturewas heated at reflux 3.5 h and allowed to stand at 24° C. for 18 h priorto concentration by rotary evaporation. The residue was dissolved inethyl acetate, washed with sat'd NaHCO₃ solution and brine.Recrystallization from methylene chloride/hexanes gave 1 g (63%) mp 200°C.; IR(KBr, υ=cm⁻¹) 3168, 3064, 1772, 1701, 1504, 1444, 1426, 1408,1260, 1190, 1150; ¹H NMR (300 MHz, CDCl₃) δ 3.59 (3H, s), 5.60 (1H, s),6.80 (1H, d, J=8.8 Hz), 7.14-7.37 (7H, m), 8.92 (1H, br.s); MS(DCl)m/z:317(MH⁺); Anal. calcd. for C₁₆H₁₃ClN₂O₃: C, 60.67; H, 4.13; N, 8.84.Found: C,60.47; H, 4.12; N, 8.80.

EXAMPLE 43 1-(5-Chloro-2-hydroxyphenyl)-5-phenyl-2,4-imidazolidinedione

(XIV⁴³)

The title phenol was prepared according to the BBr₃ method of Example37.

mp 235-236° C.; Anal. calcd. for C₁₅H₁₁ClN₂O₃: C, 59.51; H, 3.66; N,9.25. Found: C, 59.27; H, 3.66; N, 9.51.

Preparation No. 4

Oxadiazolone starting materials were prepared according to theprocedures set out in M. D. Mullican, et al. J. Med. Chem. 36, 1090(1993).

EXAMPLES 44-55

EXAMPLE 443-[[4-(Acetylamino)-5-chloro-2-methoxyphenyl]methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁴⁴: X′=Cl, Y=NHAc, R¹=R⁴=H, R²=R³=Cl)

5-(3,4-Dichlorophenyl)-1,3,4-oxadiazol-2(3H)-one (2.0 g, 8.66 mmol),N-[4-(bromomethyl)-2-chloro-5-methoxyphenyl]acetamide [JP 49049929] (2.2g, 8.67 mmol), K₂CO₃ (1.9 g,13.8 mmol) and KI (cat.) were heated atreflux in acetonitrile (50 ml) for 18 h. After being cooled, thereaction mixture was poured into water (300 ml), stirred vigourously,and filtered. Recrystallization from acetonitrile water gave pale yellowcrystals 2.2 g (57.8%). mp 200-201.5° C. IR(KBr, υ =cm⁻¹) 3340, 1804,1404, 1014, 850, 736; ¹H NMR (300 MHz, CDCl₃) δ 2.21 (3H, s), 3.83 (3H,s), 4.87 (2H, s), 7.22 (1H, s), 7.49 (1H, d, J=8.4 Hz), 7.60 (1H, dd,J=8.4 Hz, 2.0 Hz), 7.64 (1H, br.s), 7.86 (1H, d, J=2.0 Hz), 8.11(1H, s);MS(ESl)m/z: 440(M-H⁻). Anal. calcd. for C₁₈H₁₄Cl₃N₃O₄: C, 48.84; H,3.19; N, 9.49. Found: C, 49.07; H, 3.17; N, 9.61.

The following oxadiazolones were prepared in a manner similar to Example44.

EXAMPLE 453-[[4-(Acetylamino)-5-chloro-2-methoxyphenyl]methyl]-5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁴⁵: X′=Cl, Y=NHAc, R¹=R³=H, R²=R⁴=Cl)

mp 144-145° C.; Anal. calcd. for C₁₈H₁₄Cl₃N₃O₄: C, 48.84; H, 3.19; N,9.49. Found: C, 48.83; H, 3.35; N, 9.72.

EXAMPLE 463-[(4-(Acetylamino)-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁴⁶: X′=Cl, Y=NHAc, R₁=R²=R⁴=H, R³=CF₃)

mp 202-205.5° C.; Anal. calcd. for C₁₉H₁₅ClF₃N₄O₄.0.1 H₂O.0.1 THF: C,51.69; H, 3.58; N, 9.32. Found: C, 51.71; H, 3.49; N, 9.30.

EXAMPLE 473-[(4-(Acetylamino)-5-chloro-2-methoxyphenyl)methyl]-5-([1,1′-biphenyl]-4-yl)]-1,3,4-oxadiazol-2(3H)-one

(XV⁴⁷: X′=Cl, Y=NHAc, R¹=R²=H, R³=Ph)

mp 203-204° C.; Anal. calcd. for C₂₄H₂₀ClN₃O₃: C, 64.07; H, 4.48; N,9.34. Found: C, 64.02; H, 4.52; N, 9.21.

EXAMPLE 483-[(4-(Acetylamino)-5-chloro-2-methoxyphenyl)methyl]-5-(2-naphthalenyl)-1,3,4-oxadiazol-2(3H)-one

(XV⁴⁸: X′=Cl, Y=NHAc, R¹=R⁴=H, R³=R⁴=—C₂H₂—)

mp 209-211° C.; Anal. calcd. for C₂₂H₁₈ClN₃O₄: C,62.34; H, 4.28; N,9.91. Found: C, 62.15; H, 4.37; N, 10.02.

EXAMPLE 493-[2-Methoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁴⁹: X′=H, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 107.5-108.5° C.; Anal. calcd. for C₁₇H₁₃F₃N₂O₃: C, 58.29; H, 3.74; N,8.00. Found: C, 58.30; H, 3.61; N, 7.90.

EXAMPLE 503-[(5-Chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁵⁰: X′=Cl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 144-145° C.; Anal. calcd. for C₁₇H₁₂ClF₃N₂O₃.0.1 H₂O: C, 52.81; H,3.19; N, 7.25. Found: C, 53.03; H, 3.20; N, 7.31.

EXAMPLE 513-[(2-Methoxy-5-chlorophenyl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁵¹: X′=Cl, Y=H, R¹=R³=H, R²=R⁴=CF₃)

mp 127-128° C.; Anal. calcd. for C₁₈H₁₁ClF₆N₂O₃: C, 47.75; H, 2,45; N,6.19. Found: C, 47.83; H, 2,42; N, 6.17.

EXAMPLE 523-[[2-Methoxy-5-chlorophenyl]methyl]-5-[2-chloro-5-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁵²: X′=Cl, Y=H, R¹=Cl, R³=R²=H, R⁴=CF₃)

mp 151-152° C.; Anal. calcd. for C₁₇H₁₁Cl₂F₃N₂O₃: C, 48.71; H, 2.64; N,6.68. Found: C, 48.39; H, 2.36; N, 6.78.

EXAMPLE 533-[[2-Methoxy-5-chlorophenyl]methy]5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁵³: X′=Cl, Y=H, R¹=Cl, R¹=R³=H, R²=R⁴=Cl)

mp 172-173° C.; Anal. calcd. for C₁₆H₁₁Cl₃N₂O₃: C, 49.83; H, 2.87; N,7.26. Found: C, 49.75; H, 2.86; N, 7.31.

EXAMPLE 543-[(5-Chloro-2-methoxyphenyl)methyl]-5-[2-fluoro-4-(trifluoromethyl)-phenyl]1,3,4-oxadiazol-2(3H)-one

(XV⁵⁴: X′=Cl, Y=H, R¹=F, R¹=R³=H, R²=R⁴=CF₃)

mp 126-128° C.; Anal. calcd. for C₁₇H₁₁ClF₄N₂O₃: C, 50.70; H, 2.75; N,6.96. Found: C, 50.55; H, 2.66; N, 7.07.

EXAMPLE 553-[(5-Chloro-2-methoxyphenyl)methyl]-5-[4-fluoro-3-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁵⁵: X′=Cl, Y=H, R¹=R⁴=H, R²=CF₃, R³=F)

mp 118-119° C.; Anal. calcd. for C₁₇H₁₁ClF₄N₂O₃: C, 50.70; H, 2.75; N,6.96. Found: C, 50.70; H, 2.72; N, 7.01.

EXAMPLES 56 AND 57

EXAMPLE 563-[(5-Chloro-2-methoxyphenyl)methyl]-5-[2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XVII⁵⁶)

3-[(5-Chloro-2-methoxyphenyl)methyl]-5-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1.2 g, 2.97 mmol) and imidazole (269mg, 3.95 mmol) were taken up in DMF (7 ml) under N₂ at room temperatureand (135 mg, 4.6 mmol) sodium hydride (80%) was added in portions andthe reaction mixture was heated at 80° C. for 3 h. The solution wasdiluted with saturated ammonium chloride solution and extract with ethylacetate. The organic phase was washed with water, brine, and dried overMgSO₄. Concentration onto SiO₂, elution with 15% ethylacetate/chloroform gave 1.16 g (61%).

mp 143.5-151° C.; Anal. calcd. for C₂₀H₁₄ClF₃N₄O₃: C, 53.29; H, 3.13; N,12,43. Found: C, 53.36; H, 2.95; N, 12.24.

The following imidazole was prepared in a similar manner to Example 56.

EXAMPLE 573-[(5-Chloro-2-methoxyphenyl)methyl]-5-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XVII⁵⁷)

mp 148-150° C.; Anal. calcd. for C₂₀H₁₄ClF₃N₄O₃: C, 53.29; H, 3.13; N,12,43. Found: C, 53.15; H, 3.10; N, 21.24.

EXAMPLE 58 4-(Acetylmethylamino)-5-chloro-2-methoxybenzoic acid, methylester

4-(Acetylamino)-5-chloro-2-methoxybenzoic acid, methyl ester (10.0 g,38.08 mmol) was dissolved in anhydrous THF (250 ml) under N₂ and 1.23 gof sodium hydride (80%, 41.0 mmol) added in portions. Methyl iodide (2.5ml, 40.1 mmol) was added and the reaction mixture heated at reflux for 5h during which time additional Mel and NaH were added to drive thereaction to completion. Water was added, and the solution wasconcentrated by rotary evaporation and the residue taken up in ethylacetate and washed with brine and dried over MgSO₄. Chromatography onSiO₂, elution with 55% ethyl acetate/hexanes gave 4.77 g (45%); mp105.5-107° C.; IR(KBr, υ=cm⁻¹) 3040, 1712, 1662, 1242; ¹ H NMR (300 MHz,DMSO-d₆) δ 1.72 (3H, s), 3.07 (3H, s), 3.79 (3H, s), 3.84 (3H, s), 7.41(1H, s), 7.81 (1H, s); MS(DCl)m/z: 272 (MH⁺). Anal. calcd. forC₁₂H₁₄ClNO₄: C, 53.05; H, 5.19; N, 5.15. Found: C, 53.05; H, 5.05; N,4.96.

EXAMPLE 59 4-(Ethylmethylamino)-5-chloro-2-methoxybenzenemethanol

4-(Acetylmethylamino)-5-chloro-2-methoxybenzoic acid, methyl ester (2 g,7.36 mmol) was taken up in anhydrous THF (50 ml) and 40 ml ofdiethylether. Lithium aluminum hydride (558 mg, 14.7 mmol) was added inportions and the reaction mixture stirred for 2 h before being cooled to0° C. and quenched with 1N sodium hydroxide solution. The resultingsuspension was filtered and the filtered salts washed extensively withTHF. The filtrate was concentrated by rotary evaporation to give 1.6 g(89.5%) of an oil found to be a 5:1 mixture of product to4-(acetylmethylamino)-5-chloro-2-methoxybenzenemethanol. Product: ¹H NMR(300 MHz, DMSO-d₆) δ 1.06 (3H, t, J=7.03 Hz),2.69 (3H, s), 3.01 (2H, q,J=7.0 Hz), 3.77 (3H, s), 4.39 (2H, d, J=5.7 Hz), 5.01 (1H, t, J=5.7 Hz),6.69 (1H, s), 7.27 (1H, s).

EXAMPLE 60 2-Methoxy-5-(4-morpholinylmethyl)benzenemethanol

Step A: 4-[(4-Methoxyphenyl)methyl]morpholine Intermediate

4-Methyoxybenzylchloride (25 g, 0.16 mol), morpholine (14 g, 0.16 mol),and potassium carbonate (22 g, 0.16 mol) were taken up in acetonitrileand Kl (8.7 g, 0.04 mol) added. The reaction mixture was heated atreflux for 18 h, filtered, and the filtrate concentrated and azeotroppedwith benzene to give 17.5 g (88%) as an oil; IR(film, υ=cm⁻¹) 2956,2806, 1514, 1246, 1118, 866; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (4H, br.s), 3.35 (2H, s), 3.53 (4H, t, J=4.4 Hz), 3.71 (3H, s), 6.86 (2H, d,J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz); MS(DCl)m/z: 208 (MH⁺).

Step B: 2-Methoxy-5-(4-morpholinylmethyl)benzenemethanol

4-[(4-Methoxyphenyl)methyl]morpholine (5 g, 24.1 mmol), and co-solventN, N, N′, N′, N″-pentamethyidiethylenetriamine (PMDTA) (5.4 ml, 26.0mmol) were cooled to −78° C. in anhydrous THF under N₂ and 20 ml ofsec-BuLi (1.3 M, 26.0 mmol) added via syringe. The reaction mixture wasstirred 2 h and DMF (3.5 ml, 40 mmol) was added followed by slow warmingto room temperature. The solution was concentrated and the residue takenup in ethyl acetate and washed with brine and dried.

The resultant aldehyde was taken up in methanol (500 ml) under N₂ andsodium borohydride (875 mg, 23.0 ml) was added in portions at roomtemperature. After being stirred 4.5 h, water (20 ml) was added and thesolution concentrated by rotary evaporation. The residue was partitionedbetween ethyl acetate and water and the organic phase washed with brine.Chromatography on SiO₂, elution with methanol/ethyl acetate/hexanes(1:2:7) gave 2.3 g (40%) of the alcohol as an oil; IR(film, υ=cm⁻¹)3400, 2810, 1612, 1500, 1250, 1116, 1034; ¹H NMR (300 MHz, DMSO-d₆) δ2.30 (4H, br. s), 3.36 (2H, s), 3.54 (4H, t, J=5.6 Hz), 3.73 (3H, s),4.46 (2H, d, J=5.6 Hz), 4.99 (1H, t, J=5.6 Hz), 6.85 (1H, d, J=8.3 Hz)7.10 (1H, dd, J=8.2 Hz, 1.6 Hz), 7.30 (1H, s); MS(DCl)m/z: 238 (MH⁺).

EXAMPLE 61 5-(1H-imidazol-1-yl)-2-methoxybenzoic acid, methyl ester

5-Bromo-2-methoxybenzoic acid, methyl ester (5 g, 20.4 mmol), imidazole(1.4 g, 20.6 mmol), and potassium carbonate (2.9 g, 20.7 mmol) wereheated to 145° C. in DMF under N₂ as cuprous iodide (1.5 g, 7.9 mmol)was added in portions. The reaction was stirred at this temperature for18 h, allowed to cool, and filtered through a celite plug. The filteredsalts were washed extensively with methanol, the filtrate concentratedin vacuo, and the residue taken up in ethyl acetate, washed with water,brine, and dried. Chromatography on SiO₂, elution with methanol/ethylacetate/hexanes (1:1:3) gave 3 g (63%); IR(KBr, υ=cm⁻¹) 3430, 1726,1512, 1232, 1068; ¹H NMR (300 MHz, DMSO-d₆) δ 3.80 (3H, s), 3.85 (3H,s), 7.07 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.69 (1H, s), 7.76 -7.82 (2H,m) 8.18 (1H, s); MS(DCl)m/z: 233 (MH⁺).

EXAMPLE 62 5-(1H-Imidazol-1-yl)-2-methoxybenzenemethanol

5-(1H-Imidazol-1-yl)-2-methoxybenzoic acid, methyl ester (2 g, 8.6 mmol)was cooled to 0C in anhydrous THF under N₂ and LiAlH₄ was added. Thereaction mixture stirred for 18 h at 24° C,. and water (0.7 ml) followed15% sodium hydroxide solution (0.7 ml) and water (0.7 ml) wassequentially added dropwise. The resultant suspension was filtered andconcentrated to give 1.3 g (74%); ¹H NMR (300 MHz, DMSO-d₆) δ 3.81(3H,s), 4.52 (2H, d, J=4.3 Hz), 5.18 (1H, br. s), 7.04 -7.06 (2H, m), 7.43(1H, dd, J=8.7 Hz, 2.8 Hz), 7.52 (1H, d, J=2.8 Hz) 7.58 (1H, s), 8.07(1H, s); MS(DCl)m/z: 205 (MH⁺).

EXAMPLE 63 2-Methoxy-5-(1-methyl-1H-imidazol-2-yl)benzenemethanol

Step A:[(5-Bromo-2-methoxyphenyl)methoxy]dimethyl(1,1-dimethylethyl)silane

5-Bromo-o-anisaldehyde (30 g, 0.14 mol) was dissolved in THF (30 ml) and500 ml of methanol. Sodium borohydride (8 g, 0.21 mol) was added inportions over 10 min. and the solution stirred for 3 h and quenched with5% HCl solution. The solvent was removed by rotary evaporation and theresidue taken up in ethyl acetate, washed with 1N HCl solution, water,and brine before drying over MgSO₄. Concentration gave an oil 29.4 g(97.2%).

The alcohol (20.0 g, 0.092 mol), t-butyldimethylsilyl chloride (15.28 g,0.10 mol), and imidazole (13.82 g, 0.20 mol) were stirred in DMF (100ml) for 18 h. The solution was poured into water (250 ml) and extractedwith hexanes/diethylether (1:2). The organic phase was washed with 1NHCl solution, water, brine, and dried over MgSO₄. Concentration gave anoil which crystallized on standing 29.9 g (98%); mp 28-29.5° C.; IR(KBr,υ=cm⁻¹) 2954, 2930, 1488, 1464, 1258, 1094; ¹H NMR (300 MHz, DMSO-d₆) δ0.06 (6H, s), 0.89 (9H, s), 3.75 (3H, s), 4.63 (2H, s), 6.90 (1H, d,J=8.6 Hz), 7.37 (1H, dd, J=8.6 Hz, 2.6 Hz), 7.42 (1H, d, J=2.5 Hz);MS(DCl)m/z: 331 (MH⁺).

Anal. calcd. for C₁₄H₂₃BrO₂Si: C, 50.75; H, 7.00. Found: C, 50.89; H,6.95.

Step B: 2-Methoxy-5-(1-methyl-1H-imidazol-2-yl)benzenemethanol

n-Butyllithium (5.2 mL of 2.5 M in hexanes) was added dropwise toN-methyl imidazole (2 g, 24.4 mmol) in THF (26 mL) under N₂ at −78° C.,and the solution stirred 2.5 h before zinc chloride (3.33 g, 24.4 mmol)dissolved in 22 mL of the same solvent was added and the cold bath wasremoved. After 30 min, tetrakis (triphenylphosphine)palladium (0) (172mg, 0.15 mmol) was added followed by a THF solution (14 ml) of[(5-bromo-2-methoxyphenyl)methoxy]dimethyl(1,1-dimethylethyl)silane (9.7g, 29.3 mmol). The reaction mixture was stirred at reflux 2 h, cooled toroom temperature, additional zinc chloride (6.77 g, 24.4 mmol) dissolvedin 30 ml of THF added, and the solution brought back to reflux for 3 h.The solvent was removed by rotary evaporation and a solution of EDTAdisodium salt (56.4 g in 700 ml of water) was added and the pH adjustedto ˜8. The product was extrated with chloroform, and the organic phasewashed with water, brine, and dried (MgSO₄). Purification by flashcolumn chromatography on SiO₂ (elution with 35% THF/benzene) gave 4.32 g(53%).

The material was taken up in THF (45 ml) and 17 ml oftetra-n-butylammonium fluoride solution (1M in THF, 9.33 mol) addeddropwise. The reaction mixture was stirred for 4 h, ammonium chloridesolution (5 ml) added followed by saturated NaCO₃ solution, andextration into ethyl acetate. The organic phase washed with brine andconcentrated. Recrystallization from ethyl acetate gave 2.22 g (79%); mp116.5-118° C.; IR(KBr, υ=cm⁻¹) 3170, 1612, 1506, 1478, 1358, 1252, 1054;¹H NMR (300 MHz, DMSO-d₆) δ 3.69 (3H, s), 3.81 (3H, s), 4.53 (2H, d,J=5.7 Hz), 5.16 (1H, t, J=5.7 Hz), 6.92 (1H, d, J=1.1 Hz), 7.01 (1H, d,J=8.5 Hz), 7.18 (1H, d, J=1.0 Hz), 7.50 (1H, dd, J=8.5 Hz, 2.2 Hz), 7.68(1H, d, J=2.2 Hz); MS(DCl)m/z: 219 (MH⁺). Anal. calcd. for C₁₂H₁₄N₂O₂:C, 66.04; H, 6.47; N, 12.84. Found: C, 66.13; H, 6.09; N, 12.84.

EXAMPLE 64 2-Methoxy-5-(2-pyridinyl)benzenemethanol

The 2-pyridinyl derivative was prepared in a similar manner, asdescribed in Example 63.

mp 92-93° C.; IR(KBr, υ=cm⁻¹)3324, 1584, 1562, 1436, 1272, 1042, 782; ¹HNMR (300 MHz, DMSO-d₆) δ 3.82 (3H, s), 4.56 (2H, d, J=5.7 Hz), 5.13 (1H,t, J=5.7 Hz), 7.02 (1H, d, J=8.6 Hz), 7.23-7.27 (1H, m), 7.77-7.86(2H,m), 7.94 (1H, dd, J=8.6 Hz, 2,4 Hz), 8.17 (1H, d, J=2.3 Hz) 8.59-8.62 (1H, m); MS(DCl)m/z: 216 (MH⁺). Anal. calcd. for C₁₃H₁₃NO₂: C,72.54; H, 6.09; N, 6.51. Found: C,72.66; H, 6.01; N, 6.49.

EXAMPLES 65-67

EXAMPLE 653-[[2-Methoxy-5-(4-morpholinylmethyl)phenyl]methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁶⁵: X′=morpholinylmethyl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

5-[4-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1 g, 4.3 mmol),2-methoxy-(4-morpholinylmethyl)benzyl alcohol (1.05 g, 4.3 mmol), andtriphenylphosphene (1.1 g, 4.3 mmol) were dissolved in THF (100ml) at 0°C. under N₂. Diethylazodicarboxylate (0.68 ml, 4.3 mmol) was addeddropwise and the solution stirred for 18 h at 24° C. Concentration onSiO₂, and elution with 20% THF/benzene gave 1.35 g (70%) crystallizedfrom diethylether.

mp 124-125° C.; Anal. calcd. for C₂₂H₂₂F₃N₃O₄: C, 58.80; H, 4.93; N,9.35. Found: C, 58.70; H, 4.81; N, 9.16.

The following oxadiazolones were prepared by a Mitsunobu proceduresimilar to Example 65.

EXAMPLE 663-[5-Chloro-4-[(ethylmethylamino)-2-methoxyphenyl]methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁶⁶: X′=ethylmethylamino, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 105-107° C.; Anal. calcd. for C₂₀H₁₉ClF₃N₃O₃: C, 54.37; H, 4.33; N,9.51. Found: C, 54.27; H, 4.32; N, 9.41.

EXAMPLE 673-[[2-Methoxy-5-(2-pyridinyl)phenyl]methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁶⁷: X′=2-pyridinyl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 165-166° C.; Anal. calcd. for C₂₂H₁₆F₃N₃O₃: C, 61.83; H, 3.77; N,9.83. Found: C, 60.48; H, 3.87; N, 9.66.

EXAMPLES 68 AND 69

EXAMPLE 683-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XVI⁶⁸: R¹=R⁴=H, R²=R³=Cl)

N-[2-Chloro-4-[[1,5-dihydro-5-oxo-3-[3,4-dichlorophenyl]-1,2,4-oxadiazol-1-yl]methyl]-5-methoxyphenyl]acetamide(1 g, 2,45 mmol) was taken up in absolute ethanol (110 ml) andconcentrated HCl solution (11 ml) added and the reaction mixture heatedat reflux for 1 h. The solvent was removed by rotary evaporation and theresidue taken up in ethyl acetate (some THF added to dissolve) andwashed with NaHCO₃ solution, brine, and dried (MgSO₄). Concentrationgave 903 mg (92%). mp 196-197.5° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 3.69(3H, s), 4.74 (2H, s), 6.57 (1H, s), 6.68 (3H, Br.s), 7.17 (1H, s), 7.70(1H, dd, J=8.4 Hz, 1.9 Hz), 7.77 (1H, d, J=8.4 Hz), 7.89 (1H, d, J=1.9Hz). ¹³CNMR (75 MHz, DMSO-d₆) δ 156.70, 152.43, 150.49. 144.06, 134.23,132.23, 131.65, 130.15, 126.90, 125.41, 124.04, 112.81, 109.16, 99.40,55.63, 44.06; MS(DCl)m/z: 400(MH⁺).

EXAMPLE 693-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one,Hydrochloride Salt

(XVI⁶⁹: R¹=R²=R⁴=H, R³=CF₃)

The title aniline was prepared in a similar manner to Example 68.

mp>190° C. (dec); Anal. calcd. for C₁₇H₁₃ClF₃N₃O₃.1.0 HCl: C, 46.81; H,3.24; N, 9.63. Found: C, 46.97; H, 3.19; N, 9.54.

EXAMPLES 70-74

EXAMPLE 702-Bromo-N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadizol-3-yl]methyl]-5-methoxyphenyl]acetamide

(XIX⁷⁰: Q_(N)=Br)

3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (3 g, 7.5 mmol) and pyridine (0.68 ml,8.41 mmol) were dissolved in THF (35 ml) under N₂ and cooled to 0° C.Bromoacetyl bromide (0.72 ml, 8.26 mmol) was added dropwise and thereaction mixture stirred for 18 h at 24° C. before being partitionedbetween ethyl acetate (400 ml) and 0.1N HCl solution (50 ml). Theorganic phase was washed with saturated NaHCO₃ solution and brine, anddried over MgSO₄. Active carbon (500 mg) was added and the solutionfiltered through a plug of Celite. Concentration gave 3.8 g (98%); mp140-182° C. (dec); IR(KBr, υ=cm⁻¹) 3348, 2972, 1784, 1672, 1594, 1234,1168, 1066; ¹H NMR (300 MHz, DMSO-d₆) δ 3.77 (3H, s), 4.15 (2H, s), 4.90(2H, s), 7.47-7.48 (2H, m), 7.86 (2H, d, J=8.4 Hz), 7.96 (1H, d, J=8.3Hz), 9.30 (1H, s); MS(ESI)m/z: 520(MH⁺); Anal. calcd. forC₁₈H₁₄BrClF₃N₃O₄: C, 43.83; H, 2.71; N, 8.07. Found: C, 43.68; H, 2.54;N, 7.77.

EXAMPLE 71N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-methoxyphenyl]-4-morpholineacetamide

(XIX⁷¹: Q_(N)=morpholine)

2-Bromo-N-[2-Chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadizol-1-yl]methyl]-5-hydroxyphenyl]acetamide (1 g, 1.9 mmol), morpholine (167 mg, 1.9 mmol), potassiumcarbonate (262 mg, 1.9 mmol) and Kl (78 mg) were dissolved inacetonitrile (100 ml) and heated at reflux for 3.5 h. The reactionmixture was filtered, concentrated by rotary evaporation, and theresidue taken up in ethyl acetate and washed with water and brine.Recrystallization from acetonitrile gave 900 mg (90%). mp 178-179° C.;IR(KBr, υ=cm⁻¹) 3434, 2848, 1772, 1696, 1528, 1324, 1118; ¹H NMR (300MHz, DMSO-d₆) 67 2.56 (4H, br. s), 3.18 (2H, s), 3.65 (4H, t, J=4.3 Hz),3.78 (3H, s), 4.88 (2H, s), 7.50 (1H, s), 7.88 (2H, d, J=8.5 Hz), 7.96(2H, d, J=8.4 Hz), 8.04 (1H, s), 9.94 (1H, s); MS(ESI)m/z: 527 (MH⁺);Anal. calcd. for C₂₃H₂₂ClF₃N₄O₅: C, 52,43; H, 4.21; N, 10.63. Found: C,52.31; H, 4.08; N, 10.56.

The compounds of Examples 72-74 were prepared in a manner similar tothat of Example 71.

EXAMPLE 72N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-methoxyphenyl]-4-methyl-1-piperazineacetamide

(XIX⁷²: Q_(N)=N-methylpiperazine)

mp 190.5-192.5° C.; Anal. calcd. for C₂₄H₂₅ClF₃N₅O₄: C, 53.39; H, 4.67;N, 12.97. Found: C, 53.34; H, 4.72; N, 12.80.

EXAMPLE 73N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-methoxyphenyl]-4-phenyl-1-piperazineacetamide

(XIX⁷³: Q_(N)=N-phenylpiperazine)

mp 228-230° C.; Anal. calcd. for C₂₉H₂₇ClF₃N₅O₄: C, 57.89; H, 4.52; N,11.63. Found: C, 57.90; H, 4.54; N, 11.59.

EXAMPLE 74N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-methoxyphenyl]-2-(dimethylamino)acetamide

(XIX⁷⁴: Q_(N)=dimethylamine)

mp 140.5-143.5° C.; Anal. calcd. for C₂₁H₂₀ClF₃N₄O₄.0.1 H₂O: C, 51.81;H, 4.19; N, 11.51. Found: C, 51.42; H, 4.24; N, 10.90.

EXAMPLE 753-[(5-Chloro-2-methoxyphenyl)methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-thione

(XVIII⁷⁵)

3-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one(1 g, 2.7 mmol) and Lawesson's reagent (800 mg, 1.98 mmol) were heatedat reflux in toluene (50 ml) for 18 h. An additional 400 mg of reagentwas added and the reaction heated at reflux 48 h. Concentration on SiO₂and elution with 10% ethyl acetate/hexanes gave an oil. Crystallizationoccurred upon standing in diethylether/ethyl acetate and gave 800 mg(77%). mp 158-159° C.; IR(KBr, υ=cm⁻¹) 3456, 1608, 1492, 1450, 1332,1318, 1250, 1166, 1112; ¹H NMR (300 MHz, DMSO-d₆) δ 3.82 (3H, s), 5.27(2H, s), 7.08 (1H, d, J=8.6 Hz), 7.34-7.40 (2H, m), 7.93 (2H, d, J=8.5Hz), 8.07 (2H, d, J=8.3 Hz); MS(DCl)m/z: 401 (MH⁺); Anal. calcd. forC₁₇H₁₂ClF₃N₂O₂S: C, 50.94; H, 3.02; N, 6.99. Found: C, 50.87; H, 3.00;N, 7.04.

EXAMPLES 76 AND 77

EXAMPLE 763-[[5-Chloro-4-(2,3-dihydro-2-oxo-1H-imidazol-1-yl)-2-methoxyphenyl]-methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XX⁷⁶: X=O)

3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1.14 g, 2.9 mmol) and triethylamine(1.0 ml, 6.8 mmol) were taken up in anhydrous THF (20 ml) andtransferred dropwise by cannula into a 20% solution of phosgene intoluene at 0° C. under N₂. The reaction was stirred 2.5 h at 24° C.,diluted with diethylether (1 vol), and filtered through a celite plug.Concentrated by rotary evaporation to gave a solid which was dissolvedin dichloromethane (50 ml) under N₂ and aminoacetaldehyde (0.42 ml, 2.9mmol) was added. The solution was stirred 3 h and concentrated to removesolvent. The residue was taken up in 25 ml of formic acid (88%) andstirred 18 h at 24° C. The formic acid was removed by rotary evaporationthe residue taken up in ethyl acetate, washed with saturated NaHCO₃solution and brine, and dried. Concentration on SiO₂, and elution with45% THF/benzene gave 850 mg (65%). mp 201-202° C.; IR(KBr, υ=cm⁻¹)3414,1792, 1694, 1330, 1236, 1136; ¹H NMR(300 MHz, CDCl₃) δ 3.86 (3H, s),4.97 (2H, s), 6.38 (2H, br. s), 6.99 (1H, s), 7.40 (1H, s), 7.71 (2H, d,J=8.4 Hz), 7.94 (2H, d, J=8.2 Hz), 10.28 (1H, br. s); MS(ESI)m/z: 465(M-H⁻); Anal. calcd. for C₂₀H₁₄ClF₃N₄O₄.0.1 H₂O: C, 51.20; H, 3.06; N,11.94. Found: C, 51.18; H, 3.10; N, 11.99.

EXAMPLE 773-[[5-Chloro-4-(2,3-dihydro-2-thio-1H-imidazol-1-yl)-2-methoxyphenyl]-methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XX⁷⁷: X=S)

The title compound was prepared in a similar manner to Example 76 usingthiophosgene in place of phosgene.

mp 184-185° C.; Anal. calcd. for C₂₀H₁₄ClF₃N₄O₃S: C, 49.75; H, 2.92; N,11.60. Found: C, 49.56; H, 2.82; N, 11.53.

EXAMPLES 78-80

EXAMPLE 783-[(4-Amino-5-chloro-2-hydroxyphenyl)methyll-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XVI⁷⁸: R¹=R⁴=H, R²=R³=Cl)

3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one(903 mg, 2.25 mmol) was taken up in dichloromethane (55 ml) and cooledto 0° C. under N₂ and 12 ml of boron tribromide (1.0 M in CH₂Cl₂) wasadded. The reaction mixture was stirred for 18 h at 24° C. and poureddropwise into 200 ml of saturated NaHCO₃ solution at 0° C. with rapidstirring. The product was extracted with ethyl acetate (some THF addedfor solubility), washed with brine, and dried over MgSO₄. Triturationwith boiling methanol gave 853 mg (97%); mp 202-203° C.; IR(KBr, υ=cm⁻¹)3364, 3296, 1804, 1166, 738; ¹H NMR (300 MHz, DMSO-d₆) δ 4.72 (2H, s),5.31 (2H, s), 6.29 (1H, s), 7.04 (1H, s), 7.71 (1H, dd, J=8.4 Hz, 2.0Hz), 7.78 (1H, d, J=8.4 Hz), 7.90 (1H, d, J=1.9 Hz), 9.57 (1H, s);MS(ESI)m/z: 384 (M-H⁻); Anal. calcd. for C₁₅H₁₀Cl₃N₃O₃: C, 46.60; H,2.61; N, 10.87. Found: C, 46.56; H, 2.52; N, 10.62.

The following phenols, Examples 79 through 107, were prepared by theBBr₃ method of example 78.

EXAMPLE 793-[[4-(Amino)-5-chloro-2-hydroxyphenyl]methyl]-5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XVI⁷⁹: R¹=R³=H, R²=R⁴=Cl)

mp 219-220° C.; Anal. calcd. for C₁₅H₁₀Cl₃N₃O₃: C, 46.60; H, 2.61; N,10.87. Found: C, 46.49; H, 2.80; N, 10.65.

EXAMPLE 803-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XVI¹⁸⁰: R¹=R²=R⁴=H, R³=CF₃)

mp 210-212° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₃.0.1 H₂O; 0.1 CH₃CN: C,49.68; H, 2.96; N, 11.09. Found: C, 49.68; H, 2.73; N, 10.99.

EXAMPLES 81-87

EXAMPLE 813-[2-Hydroxyphenyl)methyl]-5-[4-(trifluoromethyl]phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸¹: X′=H, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 181-182° C.; Anal. calcd. for C₁₆H₁₁F₃N₂O₃: C, 57.15; H, 3.30; N,8.33. Found: C, 57.14; H, 3.35; N, 8.19.

EXAMPLE 823-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸²: X′=Cl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 217-218° C.; Anal. calcd. for C₁₆H₁₀ClF₃N₂O₃: C, 51.84; H, 2.72; N,7.56. Found: C, 51.88; H, 2.58; N, 7.57.

EXAMPLE 833-[[2-Hydroxy-5-chlorophenyl]methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸³: X′=Cl, Y=H, R¹=R³=H, R³=R⁴=CF₃)

mp 171-172° C.; Anal. calcd. for C₁₇H₉ClF₆N₂O₃: C, 46.54; H, 2.07; N,6.39. Found: C, 46.82; H, 2.07; N, 6.30.

EXAMPLE 843-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-fluoro-3-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸⁴: X′=Cl, Y=H, R¹=R⁴=H, R²=CF₃, R⁴=F)

mp 163.5-165.5° C.; Anal. calcd. for C₁₆H₉ClF₄N₂O₃: C, 49.44; H, 2.30;N, 7.21. Found: C, 49.15; H, 2.16; N, 7.17.

EXAMPLE 853-[[2-Hydroxy-5-chlorophenyl]methyl]-5-[2-chloro-5-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸⁵: X′=Cl, Y=H, R¹=Cl, R²=R³=H, R⁴=CF₃)

mp 177-179° C.; Anal. calcd. for C₁₆H₉Cl₂F₃N₂O₃: C, 47.43; H, 2.24; N,6.91. Found: C, 47.40; H, 2.24; N, 6.96.

EXAMPLE 863-[[2-Hydroxy-5-chlorophenyl]methyl]-5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸⁶: X′=Cl, Y=H, R¹=R³=H, R²=R⁴=Cl)

mp 207-209° C.; Anal. calcd. for C₁₅H₉Cl₃N₂O₃: C, 48.48; H, 2,44; N,7.54. Found: C, 48.51; H, 2.37; N, 7.61.

EXAMPLE 873-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[2-fluoro-4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁸⁷: X′=Cl, Y=H, R¹=F, R²=R⁴=H, R³=CF₃)

mp 202-204.5° C.; Anal. calcd. for C₁₆H₉ClF₄N₂O₃.0.1 EtOAc: C, 49.55; H,2,49; N, 7.05. Found: C, 49.57; H, 2.51; N, 6.91.

EXAMPLES 88 AND 89

EXAMPLE 883-[(4-Acetylamino)-3,5-dichloro-2-hydroxyphenyl)methyl]-5-[3,4-dichlorophenyl]1,3,4-oxadiazol-2(3H)-one

(XVII⁸⁸: Y=NHAc, R¹=R⁴=H, R²=R³=Cl)

3-[[4-(Acetylamino)-5-chloro-2-methoxyphenyl]methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one(2 g, 4.3 mmol) was taken up in dichloromethane (75 ml) and cooled to 0°C. under N₂ and 20 ml of boron tribromide (1.0 M in CH₂Cl₂) was added.The reaction mixture was stirred for 18 h at 24° C. and poured dropwiseinto 250 ml of saturated NaHCO₃ solution at 0° C. with rapid stirring.The product was extracted with ethyl acetate and THF (added forsolubility), washed with brine, and dried over MgSO₄ gave 1.9 g (98%).

The resulting phenol (1 g, 2.3 mmol) was taken up in toluene (150 ml)and catalytic diisobutylamine (3.5 μl) added followed by sulfurylchloride (0.3 ml, 3.7 mmol). The solution was heated at 68° C. over aperiod of 72 h during which time additional sulfuryl chloride (1.63 ml,20.3 mmol) was added until the reaction was complete. The precipitatewas filtered, washed with toluene, and dried to give 879 mg (81%).Recrystallization gave: mp 246-247° C.; IR(KBr, υ=cm⁻¹) 3379, 3231,1780, 1657, 1473, 1409, 1134; ¹H NMR (300 MHz, DMSO-d₆) δ 2.05 (3H, s),4.97 (2H, s), 7.45 (1H, s), 7.73-7.81 (2H, m), 7.92-7.96 (1H, 9.81 (1H,s), 10.01 (1H, s); MS(ESI)m/z: 460 (M−H⁻). Anal. calcd. forC₁₇H₁₁Cl₄N₃O₄.0.05 H₂O: C,44.01; H, 2,41; N, 9.06. Found: C, 43.85; H,2.33; N, 9.23.

The chlorination was performed according to the procedure described inR. A. Sheldon, etal. Tet. Lett. 36, 3893 (1995).

EXAMPLE 893-[(4-Amino-3,5-dichloro-2-hydroxyphenyl)methyl]-5-[3,4-dichlorophenyl]1,3,4-oxadiazol-2(3H)-one

(XVII⁸⁹: Y=NH₂, R¹=R⁴=H, R²=R³=Cl)

3-[(4-Acetylamino)-3,5-dichloro-2-hydroxyphenyl)methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one(521 mg, 1.1 mmol) was taken up in absolute ethanol (60 ml) andconcentrated HCl solution (12 ml) was added. The solution was heated atreflux over a period of 22 h during which time additional hydrochloricacid (6 ml) was added until the reaction was complete. After cooling,the precipitate was filtered and dried to give 299 mg (63%); mp200.5-202° C.; IR(KBr, υ=cm⁻¹) 3343, 1780, 1609, 1447, 1289, 1214, 1166;¹H NMR (300 MHz, DMSO-d₆) δ 4.83 (2H, s), 5.48 (2H, s), 7.17 (1H, s),7.69-7.73 (1H, m), 7.75-7.78 (1H, m), 7.90-7.81 (1H, m), 9.49 (1H, s).MS(ESI)m/z: 418 (M-H⁻). Anal. calcd. for C₁₅H₉C₄N₃O₄: C, 42.79; H,2.16;N, 9.98; Cl, 33.68. Found: C, 42.71; H, 2.09; N, 9.77; Cl, 34.11.

EXAMPLES 90 AND 91

EXAMPLE 903-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XVIII⁹⁰: 2-lm, 4-CF₃)

mp 242-243° C.; Anal. calcd. for C₁₉H₁₂F₃N₄O₃: C, 52.25; H, 2.77; N,12.83. Found: C, 51.99; H, 2.72; N, 12,46.

EXAMPLE 913-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XVIII⁹¹: 4-lm, 3-CF₃)

mp 178-180° C.; Anal. calcd. for C₁₉H₁₂F₃N₄O₃.0.25 H₂O;.0.1 EtOAc: C,51.77; H, 2.98; N, 12,45. Found: C, 51.60; H, 2.73; N, 12,44.

EXAMPLES 92-98

EXAMPLE 923-[[2-Hydroxy-5-(4-morpholinylmethyl)phenyl]methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁹²: X′=morpholinylmethyl, Y=H, R¹=R²=R⁴=H, R³=CF₃) Foam.

Anal. calcd. for C₂₁H₂₀F₃N₃O₄.0.1 H₂O; .0.2 C₆H₆: C, 58.94; H, 4.32; N,9.34. Found: C, 58.97; H, 4.44; N, 8.86.

EXAMPLE 933-[5-Chloro-4-[(ethylmethylamino)-2-hydroxyphenyl]methyl]-5-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazl-2(3H)-one

(XV⁹³: X′=ethylmethylamino, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 132-133° C.; Anal. calcd. for C₁₉H₁₇ClF₃N₃O₃: C, 53.34; H, 4.01; N,9.82. Found: C, 53.09; H, 3.90; N, 9.82.

EXAMPLE 943-[[2-Hydroxy-5-(2-pyridinyl)phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁹⁴: X′=2-pyridinyl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 198-200° C.; Anal. calcd. for C₂₁H₁₄F₃N₃O₃.1.0 H₂O; .1.0 HCl: C,53.91; H, 3.66; N, 8.98. Found: C, 53.65; H, 3.55; N, 9.00.

EXAMPLE 953-[[5-(1-Methyl-1H-imidazol-2-yl)-2-hydroxyphenyl]methyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁹⁵: X′=1-methyl-1H-imidazol-2-yl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

mp 177-180° C.; Anal. calcd. for C₂₀H₁₅F₃N₄O₃.0.15 H₂O: C, 57.32; H,3.68; N, 13.37. Found: C, 57.48; H, 3.66; N, 12.95.

EXAMPLE 963-[[2-hydroxy-5-(1-methyl-1H-imidazo-2-yl)phenyl]methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁹⁶: X′=1-methyl-1H-imidazol-2-yl, Y=H, R¹=R³=H, R²=R⁴=CF₃)

mp 203-206° C.; Anal. calcd. for C₂₁H₁₄F₆N₄O₃.0.1 H₂O: C, 51.82; H,2.96; N, 11.51. Found: C, 51.63; H, 2.94; N, 11.50.

EXAMPLE 973-[[2-Hydroxy-5-(1H-imidazol-1-yl)phenyl]methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁹⁷: X′=1H-imidazol-1-yl, Y=H, R¹=R²=R⁴=H, R³=CF₃)

Anal. calcd. for C₁₉H₁₃F₃N₄O₃: C, 56.72; H, 3.26; N, 13.93. Found: C,56.63; H, 3.22; N, 13.90.

EXAMPLE 983-[[2-Hydroxy-5-(1H-imidazol-1-yl)phenyl]methyl]-5-[3,5-bis(trifluoro-methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XV⁹⁸: X′=1H-imidazol-1-yl, Y=H, R¹=R³=H, R²=R⁴=CF₃)

mp 209-211° C.; Anal. calcd. for C₂₀H₁₂F₆N₄O₃: C, 51.07; H, 2.57; N,11.91. Found: C, 50.87; H, 2,44; N, 12.01.

EXAMPLES 99-106

EXAMPLE 99N-[2-Chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-1-yl]methyl]-5-hydroxyphenyl]-4-morpholineacetamide

(XX⁹⁹: Q_(N)=morpholine)

mp 240-2410° C.; Anal. calcd. for C₂₂H₂₀ClF₃N₄O₅: C, 51.52; H, 3.93; N,10.92. Found: C, 51.49; H, 3.91; N, 10.80.

EXAMPLE 100N-[2-Chloro-4-[[(2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-thiomorpholineacetamide

(XX¹⁰⁰: Q_(N)=thiomorpholine)

mp 250-252° C.; Anal. calcd. for C₂₂H₂₀ClF₃N₄O₄S: C, 49.96; H, 3.81; N,10.59 Found: C, 50.15; H, 3.96; N, 10.35.

EXAMPLE 101N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-methyl-1-piperazineacetamide,dihydrochloride salt

(XX¹⁰¹: Q_(N)=N-methylpiperazine)

mp >220° C. (dec). Anal. calcd. for C₂₃H₂₃ClF₃N₅O₄.2.06 HCl; .0.7 EtOH;.0.2 H₂O: C, 46.02; H, 4.70; N, 11.00. Found: C, 45.97; H, 4.67; N,10.77.

EXAMPLE 102N-[2-Chloro-4-[1,2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-phenyl-1-piperazineacetamide,dihydrochloride salt

(XX¹⁰²: Q_(N)=N-phenylpiperazine)

mp 220-235° C.; Anal. calcd. for C₂₈H₂₅ClF₃N₅O₄.1.75 HCl; .0.15 H₂O:C,51.53; H, 4.17; N, 10.73. Found: C, 51.81; H, 4.33; N, 9.92.

EXAMPLE 103N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-benzyl-1-piperazineacetamide

(XX¹⁰³: Q_(N)=N-benzylpiperazine)

mp 187.5-190° C.; Anal. calcd. for C₂₉H₂₇ClF₃N₅O₄: C, 57.86; H, 4.52; N,11.63. Found: C, 57.89; H, 4.36; N, 11.53.

EXAMPLE 104N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-2-(dimethylamino)acetamide,hydrochloride salt

(XX¹⁰⁴: Q_(N)=dimethylamino)

mp>233° C. (dec). Anal. calcd. for C₂₀H₁₈CIF₃N₅O₄.1.0 HCl; 0.5 H₂O; .0.1Et₂O: C, 46.79; H, 4.04; N, 10.70. Found: C, 46.53; H, 3.99; N, 10.64.

EXAMPLE 105N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-(1,1′-biphenyl)-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-methyl-1-piperazineacetamide,bis-hydrochloride salt

(XX¹⁰⁵: CF₃=Ph, Q_(N)=N-methylpiperazine)

mp 244-247° C.; Anal. calcd. C₂₈H₂₈ClN₅O₄.2.0 HCl; .0.34H₂O: C, 54.86;H, 5.05; N, 11.42. Found: C, 54.33; H, 4.93; N, 11.10.

EXAMPLE 106N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[naphth-2-yl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-morpholineacetamide,hydrochloride salt

(XX¹⁰⁶: CF₃=benzo, Q_(N)=morpholine)

mp 170.5-176° C.; Anal. calcd. for C₂₅H₂₃ClN₄O₅.1.0 HCl; .0.5H₂O: C,55.57; H, 4.66; N, 10.37. Found: C, 55.49; H, 4.59; N, 10.21.

EXAMPLE 1073-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-thione

(XIX¹⁰⁷)

mp 192-194° C.; Anal. calcd. for C₁₆H₁₀ClF₃N₂O₂S: C, 49.69; H, 2.61; N,7.24. Found: C, 49.82; H, 2.77; N, 7.14.

EXAMPLES 108 AND 109

EXAMPLE 1083-[[5-Chloro-4-(2,3-dihydro-2-oxo-1H-imidazol-1-yl)-2-hydroxyphenyl]-methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XXI¹⁰⁸: X=O)

mp 231-233° C.; Anal. calcd. for C₁₉H₁₂ClF₃N₄O₄: C, 50.40; H, 2.67; N,12.37. Found: C, 50.18; H, 2.66; N, 12.27.

EXAMPLE 1093-[[5-Chloro-4-(2.3-dihydro-2-thio-1H-imidazol-1-yl)-2-hydroxyphenyl]-methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XXI¹⁰⁹: X=S)

mp 201-203° C.; Anal. calcd. for C₁₉H₁₂ClF₃N₄O₃S: C, 48.68; H, 2.58; N,11.95. Found: C, 48.65; H, 2.54; N, 11.84.

Preparation No. 5

The starting oxadiazoles were prepared according to the proceduredisclosed in D. H. Boschelli, et al. J. Med. Chem. 3, 1802 (1993).

EXAMPLE 110 3-Ethoxy-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole

(R₁=R₃=H, R₂=CF₃)

5-[4-(Trifluoromethyl)phenyl]1,3,4-oxadiazol-2-amine (10 g, 44 mmol) andpotassium hydroxide (7.4 g, 0.132 mol) dissoved in abs. ethanol (300 ml)were heated at reflux for 3 h. After being cooled to 24° C., thesolution was neutralized with acetic acid and concentrated by rotaryevaporation. The residue was taken up in ethyl acetate and washed withwater and brine. Recrystallization from acetonitrile/ether (2:1) gave 9g (82%); mp 151-152° C.; IR(KBr, υ=cm⁻¹) 2996, 1534, 1460, 1330, 1162,1130, 1070; ¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (3H, t, J=7.1 Hz), 4.38(2H, q, J=7.0 Hz), 7.82 (2H, d, J=8.3 Hz), 8.10 (2H, d, J=8.1 Hz), 13.64(1H, br. s); MS(DCl)m/z: 258 (MH⁺); Anal. calcd. for C₁₁H₁₀F₃N₃O: C,51,37; H, 3.92; N, 16.34. Found: C, 51.40; H, 3.74; N, 16.28.

EXAMPLE 111 3-Ethoxy-5-[3,4-dichlorophenyl]-4H-1,2,4-triazole

(R₁=R₂=Cl, R₃=H)

The title ethoxytriazole was prepared in a similar manner to Example110.

mp 165-165.5° C.; Anal. calcd. for C₁₀H₉Cl₂N₃O: C, 46.54; H, 3.51; N,16.28. Found: C, 46.49; H, 3.56; N, 16.34.

EXAMPLES 112-114

EXAMPLE 112N-[2-Chloro-4-[5-ethoxy-3-[[4-(trifluoromethyl)phenyl]methyl]-1H-1,2,4-triazol-1-yl]-methoxyphenyl]acetamide

(XXII¹¹²: Y=NHAc, R₁=H, R₂=CF₃)

3-Ethoxy-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (1.76 g, 6.8mmol) and N-[4-(bromomethyl)-2-chloro-5-methoxyphenyl]acetamide [JP49049929] (2.0 g, 6.8 mmol) were dissolved in anhydrous DMF at 24° C.and 2 eqv. (408 mg, 14 mmol) of sodium hydride (80%) was added inportions under N₂. The reaction mixture was stirred 18 h and poured intowater (2 vol) and extracted with ethyl acetate, washed with brine, anddried. Chromatography, elution with 20% THF/benzene gave gave 1.2 g(34%) of product, and 1.1 g (33%) of a regioisomer. IR(KBr, υ=cm⁻¹)3298, 1664, 1560, 1326, 1160, 1114; ¹H NMR(300 MHz, DMSO-d₆/CDCl₃) δ1,39 (3H, t, J=7.1 Hz), 2.08 (3H, s), 3.75 (3H, s), 4.53 (2H,q, J=7.1Hz), 5.07 (2H, s), 7.15 (1H, s), 7.47 (1H, s), 7.75 (2d, J=8.3 Hz), 8.07(2H, d, J=8.1 Hz), 9.48 (1H, s); MS(ESI)m/z: 469 (MH⁺). Anal. calcd. forC₂₁ H₂₀ClF₃N₄O₃: C, 53.80; H, 4.30; N, 11.95. Found: C, 53.93; H, 4.44;N, 11.85.

The following products were prepared in a similar manner to Example 112.

EXAMPLE 113N-[2-Chloro-4-[5-ethoxy-3-[[3,4-dichlorophenyl]methyl]-1H-1,2,4-triazol-1-yl]-methoxyphenyl]acetamide

(XXII¹¹³: Y=NHAc, R₁=R₂=Cl).

mp 197-198° C.; Anal. calcd. for C₂₀H₁₉Cl₃N₄O₃: C,51.14; H, 4.08; N,11.93. Found: C, 51.15; H, 4.17; N, 12.15.

EXAMPLE 1141-[(5-Chloro-2-methoxyphenyl)methyl]-5-ethoxy-3-[4-(trifluoromethyl)-phenyl]-1H-1,2,4-triazole

(XXII¹¹⁴: Y=H, R₁=H, R₂=CF₃).

mp 74-76° C.; Anal. calcd. for C₁₉H₁₇ClF₃N₃O₂: C, 55.42; H, 4.16; N,10.20. Found: C, 55.80; H, 4.43, N; 9.65.

EXAMPLES 115-117

EXAMPLE 1152-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one

(XXIII¹¹⁵: Y=NH₂, R₁=H, R₂=CF₃).

N-[2-Chloro-4-[5-ethoxy-3-[[4-(trifluoromethyl)phenyl]methyl]-1H-1,2,4-triazol-1-yl]-methoxyphenyl]acetamide(1.5 g, 3.2 mmol) was taken up in absolute ethanol (100 ml) and 10 mlconcentrated HCl solution and heated at reflux for 20 min. Upon coolinga precipitate formed which was filtered and suspended in ethyl acetate(some THF added to dissolve) and washed with NaHCO₃ solution, brine, anddried (MgSO₄). mp>270° C. (subl); IR(KBr, υ=cm⁻¹) 3442, 3344, 1680,1622, 1324, 1164, 1128, 1066; ¹H NMR (300 MHz, DMSO-d₆) δ 3.70 (3H, s),4.74 (2H, s), 5.36 (2H, s), 6.44 (1H, s), 6.89 (1H, s), 7.83 (2H, d,J=8.4 Hz), 7.95 (2H, d, J=8.2 Hz), 12,43 (1H, s); MS(ESI)m/z: 397(M-H⁻); Anal. calcd. for C₁₇H₁₄ClF₃N₄O₂.0.1 H₂O: C, 50.95; H, 3.58; N,13.98. Found: C, 50.66; H, 3.71; N, 13.44.

The following triazolones were prepared in a similar manner to Example115.

EXAMPLE 1162-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-2,4-dihydro-5-[3,4-dichlorophenyl]-3H-1,2,4-triazol-3-one

(XXIII¹¹⁶: Y=NH₂, R₁=R₂=Cl)

mp 265-268° C.; Anal. calcd. for C₁₆H₁₃Cl₃N₄O₂: C, 48.08; H, 3.28; N,14.02. Found: C, 48.71; H, 3.58; N, 13.08.

EXAMPLE 1172-[(5-Chloro-2-methoxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)-phenyl]-3H-1,2,4-triazol-3-one

(XXIII¹¹⁷: Y=H, R₁=H, R₂=CF₃)

mp 245-246° C.; Anal. calcd. for C₁₇H₁₃ClF₃N₃O₂: C, 53.21; H, 3,41; N,10.95. Found: C, 53.15; H, 3.39, N; 10.93.

The following phenols were prepared according to the BBr₃ method ofExample 78.

EXAMPLES 118-120

EXAMPLE 1182-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one

(XXIII¹¹⁸: Y=NH₂, R₁=H, R₂=CF₃)

Anal. calcd. for C₁₆H₁₂ClF₃N₄O₂.0.5 H₂O: C, 48.81; H, 3.33; N, 14.23.Found: C, 49.10; H, 3.42; N, 14.05.

EXAMPLE 1192-[(4-Amino-5-chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[3,4-dichlorophenyl]-3H-1,2,4-triazol-3-one

(XXIII¹¹⁹: Y=NH₂, R₁=R₂=Cl)

mp 290-293° C.; Anal. calcd. for C₁₅H₁₁Cl₃N₄O₂.0.1 H₂O: C, 46.48; H,2.92; N, 14.45. Found: C, 46.94; H, 2.84; N, 14.29.

EXAMPLE 1202-[(5-Chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)-phenyl]-3H-1,2,4-triazol-3-one

(XXIII¹²⁰: Y=H, R₁=H, R₂=CF₃)

mp >280° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂: C, 51.98; H, 3.00; N,11.37. Found: C, 52.01; H, 3.04, N; 11.35.

Preparation No. 6

EXAMPLE 1215-Chloro-3-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl]-2(3H)-benzoxazolone

(XXIV¹²¹)

Bromine (0.67 ml, 13 mmol) was added dropwise to a solution of4′-(trifluoromethyl)acetophenone (2.5 g, 13 mmol) in diethylether (20ml) and 1,4-dioxane (10 ml) at room temperature. Chlorzoxazone (2.19 g,13 mmol) was treated with sodium hydride (400 mg, 13 mmol) in DMF for 15min. under N₂ and transferred by cannulation into the freshly preparedsolution of bromide. The reaction mixture was stirred at 60° C. for 3 h,and poured into water (1 vol). The product was extracted with ethylacetate, and the organic layer washed with water and brine and dried.Concentration gave a solid 4.4 g (93%) which was recrystallized fromacetonitrile. mp 188-189° C.; IR(KBr, υ=cm⁻¹) 1776, 1704, 1330, 1226,1122; ¹H NMR (300 MHz, DMSO-d₆) δ 5.64 (2H, s), 7.20 (1H, dd, J=8.6 Hz,2.1 Hz), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2.1 Hz), 7.99 (2H, d,J=8.3 Hz), 8.27 (2H, d, J=8.1 Hz); MS(DCl)m/Z: 356 (MH⁺) Anal. calcd.for C₁₆H₉ClF₃NO₃: C, 54.03; H, 2.55; N, 3.94. Found: C, 53.73; H, 2,43;N, 3.88.

EXAMPLE 1221-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-4-[4-(trifluoromethyl)phenyl-2H-imidazol-2-one

(XXV¹²²)

5-Chloro-3-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl]-2(3H)-benzoxazolone (1 g, 2.8 mmol) and ammonium acetate (2.1 g, 28 mmol)were taken up in acetic acid (100 ml) and heated at 100° C. for 2 h. Thesolution was poured into water (2 vol) and extracted intodichloromethane. Concentration gave a solid which was recrystallizedfrom acetonitrile/AcOH(10:1). mp 278-279° C.; IR(KBr, υ=cm⁻¹)2980, 1668,1624, 1498, 1328, 1170, 1136, 1066; ¹H NMR (300 MHz, DMSO-d₆) δ 7.01(1H, d, J=8.7 Hz), 7.26 (1H, dd, J=8.7 Hz, 2.6 Hz), 7.46 (1 d, J=2.6Hz), 7.52 (1H, d, J=1.6 Hz), 7.72 (2H, d, J=8.6 Hz), 7.78 (2H, d, J=8.5Hz), 10.27 (1H, s), 11.27 (1H, s); MS(ESI)m/z: 355 (MH⁺). Anal. calcd.for C₁₆H₁₀ClF₃N₂O₂: C, 54.18; H, 2.84; N, 7.90. Found: C, 53.98; H,2.89; N, 7.92.

Preparation No. 7

EXAMPLE 123 4-(Acetylamino)-5-chloro-2-methoxybenzoic acid,4-(trifluoromethyl)-phenylhydrazide

(Y=NHAc, R₁=CF3, R₂=H)

Iso-butylchloroformate (1.6 ml, 16.4 mmol) was added dropwise to asolution of 4-(acetylamino)-5-chloro-2-methoxybenzoic acid (4 g, 16.4mmol) and 4-methylmorpholine (1.8 ml, 16.4mmol) in 400 ml of anhydrousTHF at 0° C. and stirred for 0.5 h at room temperature before additionof 4-(trifluoromethyl)phenylhydrazine (2.9 g, 16.4 mmol) dissolved in 80ml of the same solvent. The reaction mixture was stirred 8 h, dilutedwith ethyl acetate (1 vol), washed with water, saturated NaHCO3solution, and brine. Concentration gave a solid which was recrystallizedfrom acetonitrile 5.7 g (86%); mp 217-219° C.; IR(KBr, υ=cm⁻¹) 3410,3286, 1704, 1670, 1500, 1338, 1238, 1104; ¹H NMR (300 MHz, DMSO-d₆) δ2.15 (3H, s), 3.88 (3H, s), 6.88 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5Hz), 7.68 (1H, s), 7.76 (1H, s), 8.61 (1H, br. s), 9.62 (1H, br. s)10.01 (1H, br. s); MS(ESI)m/z: 400 (M−H⁻); Anal. calcd. forC₁₇H₁₅ClF₃N₃O₃: C, 50.82; H, 3.76; N, 10.46. Found: C, 50.68; H, 3.79;N, 10.45.

The following hydrazides were prepared using the procedure of Example123.

EXAMPLE 124 4-(Acetylamino)-5-chloro-2-methoxybenzoic acid,phenylhydrazide

(Y=NHAc, R₁=R₂=H)

mp 180-181 ° C.; Anal. calcd. for C₁₆H₁₆ClN₃O₃: C, 57.58; H, 4.83; N,12.59. Found: C, 57.44; H, 4.77; N, 12.72.

EXAMPLE 125 5-Chloro-2-methoxybenzoic acid,2-[4-(trifluoromethyl)phenyl]hydrazide

(Y=H, R₁=CF3, R₂=H)

mp 183.5-184.5° C.; Anal. calcd. for C₁₅H₁₂ClF₃N₂O₂: C, 52.27; H, 3.51;N, 8.13. Found: C, 52.17; H, 3.53; N, 8.08.

EXAMPLES 126-130

EXAMPLE 126N-[2-Chloro-4-[2,3-dihydro-2-oxo-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-5-yl]-5-methoxyphenyl]acetamide

(XXVI¹²⁶: Y=NHAc, R₁=CF3, R₂=H)

4-(Acetylamino)-5-chloro-2-methoxybenzoic acid, 4-(trifluoromethyl)phenylhydrazide (5.7 g, 14.2 mmol) was dissolved in THF (500 ml) underN₂. and 1,1′-carbonyldi-imidazole (2.3 g, 14.2 mmol) and triethylamine(1.5 ml, 14.2 mmol) added. The solution was stirred for 18 h at 24° C.before solvent was removed by rotary evaporation. The residue was takenup in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml),water (100 ml) and brine prior to drying over MgSO₄. Recrystallizationfrom acetonitrile gave 3.3 g (55%); mp 235-236° C. IR(KBr, υ=cm⁻¹) 3348,1772, 1690, 1334, 1234, 1116; ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (3H, s),3.89 (3H, s), 7.51 (1H, s), 7.79-7.93 (3H, m), 8.05 (2H, d, J=8.5 Hz),9.67 (1H, br. s); MS(ESI)m/z: 426 (M−H⁻); Anal. calcd. forC₁₈H₁₃ClF₃N₃O₄: C, 50.54; H, 3.06; N, 9.82. Found: C, 50.43; H, 3.01; N,9.88.

The following oxadiazolones were prepared in a fashion similar to thatof Example 126.

EXAMPLE 127N-[2-Chloro-4-[2,3-dihydro-2-oxo-3-phenyl]-1,3,4-oxadiazol-5-yl]-5-methoxyphenyl]acetamide

(XXVI¹²⁷: Y=NHAc, R₁=R₂=H)

mp 216-217° C.; Anal. calcd. for C₁₇H₁₄ClN₃O₄: C, 56.76; H,3.92; N,11.68. Found: C, 56.52; H, 3.76; N, 11.81.

EXAMPLE 1285-(5-Chloro-2-methoxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XXVI¹²⁸: Y=H, R₁=CF3, R₂=H)

mp 126.5-128° C.; Anal. calcd. for C₁₆H₁₀ClF₃N₂O₃: C, 51.84; H, 2.72; N,7.56. Found: C, 51.69; H, 2.77; N, 7.53.

The following anilines were by hydrolysis of the acetate according tothe procedure described in Example 68.

EXAMPLE 1295-(4-Amino-5-chloro-2-methoxyphenyl)-3-phenyl-1,3,4-oxadiazol-2(3H)-one

(XXVI¹²⁹: Y=NH₂, R₁=R₂=H)

mp 193-195° C.; Anal. calcd. for C₁₅H₁₂ClN₃O₃: C, 56.70; H, 3.81; N,13.23. Found: C,56.44; H, 3.91; N, 12.30.

EXAMPLE 1305-(4-Amino-5-chloro-2-methoxyphenyl)-3-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-one

(XXVI¹³⁰: Y=NH₂, R₁=R₂=Cl)

mp 220-221° C.; Anal. calcd. for C₁₅H₁₀Cl₃N₃O₃: C, 46.60; H, 2.61; N,10.87. Found: C, 46.31; H, 2.57; N, 10.65.

The following phenols were prepared according to the BBr₃ method ofExample 78.

EXAMPLES 131-134

EXAMPLE 1315-(4-Amino-5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-(3H)-one

(XXVI¹³¹: Y=NH₂, R₁=CF₃, R₂=H)

mp 266-268° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₃: C, 48.47; H, 2,44; N,11,30. Found: C, 48.37; H, 2.38; N, 11.42.

EXAMPLE 1325-(₄-Amino-5-chloro-2-hydroxyphenyl)-3-phenyl-1,3,4-oxadiazole-2-(3H)-one

(XXVI¹³²: Y=NH₂, R₁=R₂=H)

mp 280-282° C.; Anal. calcd. for C₁₄H₁₀ClN₃O₃: C, 55.37; H, 3.32; N,13.84. Found: C, 55.13; H, 3.38; N, 13.74.

EXAMPLE 1335-(5-Chloro-₂-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one

(XXVI¹³³: Y=H, R₁=CF3, R₂=H)

mp 214-215° C.; Anal. calcd. for C₁₅H₈ClF₃N2O₃: C, 50.51; H, 2.26; N,7.85. Found: C, 50.07; H, 2.1 1; N, 7.96.

EXAMPLE 1345-(4-Amino-5-cloro-2-hydroyphenyl)-3-[3,4-dichlorophenyl]1,3,4-oxadiazole-2-(3H)-one

(XXVI¹³⁴: Y=NH₂, R₁=R₂=Cl)

mp>300° C.; Anal. calcd. for C₁₄H₈Cl₃N₃O₃: C, 45.13; H, 2.16; N, 11.28.Found: C, 45.26; H, 2.12; N, 11.13.

Preparation No. 8

EXAMPLE 135 a-Oxo4-(trifluoromethyl)benzeneacetic acid.2-(5-chloro-2-methoxyphenyl) hydrazone

(XXVI¹³⁵: R₁=R₃=R₄=H, R₂=CF₃)

A solution of 4-bromobenzotrifluoride (22.5 g, 0.1 mol) in anhydrousdiethylether (30 ml) was added dropwise to a stirred suspension ofmagnesium turnings (3.65 g, 0.15 mol) activated with catalytic amount ofdibromoethane (0.5 ml) in ether (30 ml) over 30 min.

The mixture was heated at reflux for 2 h, allowed to cool, and addeddropwise over 30 min to a cold (−78° C.) stirred solution of dry diethyloxalate (14.6 g, 0.1 mol) in 50 ml of the same solvent. The resultantmixture was warmed to −20° C. over 1 h and maintained at +20° C. for 1hr before being acidified by slow addition of 1 N HCl. The organic layerwas washed with saturated NaHCO₃ solution, brine, and dried over Na₂SO₄.

Concentration followed by vacuum distillation gave a liquid 22.1 g(90%): bp 88-90° C. 0.75 torr.

The oxalate (12.3 g, 0.05 mol) was hydrolyzed upon being stirred with 3NNaOH (50 mL) in THF (50 mL) while being heated at feflux for 6 hr. TheTHF was removed by rotary evaporation, and the aqueous residue wascooled (0° C.) and acidified with 6N HCl. Extraction with EtOAc, washwith brine, and dry (Na₂SO₄) afforded[4-(trifluoromethyl)-phenyl]glyoxylic acid as a golden oil which uponstanding under vacuum solidified to a light yellow solid (10.2 g, 93%):mp 63-65° C.

Neat 5-chloro-2-methoxyphenylhydrazine (1.73 g, 10 mmol) was addedportionwise to a stirred solution of[4-(trifluoromethyl)phenyl]-glyoxylic acid (2.18 g, 10 mmol) in absoluteethanol and the resultant bright yellow suspension was stirred at roomtemperature for 30 min before heating at reflux for an addtional 30 min.Solvent was removed by rotary evaporation and the product recrystallizedfrom EtOAc-hexanes to afford the desired hydrazone carboxylic acid (3.57g, 96%): mp 210-212° C.; IR (KBr, cm⁻¹) 3300-2300, 1660, 1230, 1160,1116; ¹H NMR (300 MHz, DMSO-d₆) d 3.91 (3 H, s), 6.98 (1H, m), 7.10 (1H,d, J=8.7 Hz), 7.44 (1H, d, J=2.5 Hz), 7.75 (2 H, d, J=8.1 Hz), 7.92 (2H, d, J=8.1 Hz), 12.62 (1H, brd s); MS m/e 371 (M−H)⁻.

EXAMPLE 136-138

EXAMPLE 1362-(5-Chloro-2-methoxyphenyl)-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹³⁶: R₁=R₃=R₄=H, R₂=CF₃)

Diphenylphosphoryl azide (1.51 g, 5.5 mmol) was added to a stirredsolution of α-oxo-4-(trifluoromethyl)benzeneacetic acid,2-(5-chloro-2-methoxy-phenyl) hydrazone (1.86 g, 5 mmol) andtriethylamine (0.77 mL, 5.5 mmol) in dry toluene (60 mL). The resultantyellow solution was heated at reflux for 3 h, diluted with ethylacetate, and poured into saturated NaHCO₃ solution (100 mL) withvigorous stirring. After separation of the organic layer, the aqueousphase was further extracted with ethyl acetate and the combined organicextracts were washed with water, brine, and dried (Na₂SO₄). Evaporationof the solvents followed by trituration with warm ether gave a whitesolid 1.69 g (91%): mp 251-253° C.; IR (KBr, cm⁻¹) 2900, 1700, 1330,1290, 1130; ¹H NMR (300 MHz, DMSO-d₆) δ 3.79 (3H, s), 7.23 (1H, dd,J=8.1, 1.2 Hz), 7.51 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=1.2 Hz), 7.88(2H, d, J=8.2 Hz), 12.6 (1H, br s); MS (DCl)m/z: 370 (MH⁺). Anal. calcd.for C₁₆H₁₁ClF₃N₃O₂.0.17H₂O: C, 51.55; H, 3.06; N, 11.27. Found: C,51.54; H, 2.94; N, 11.07.

The compounds of the following Examples were prepared according to themethod in Example 136.

EXAMPLE 1372-(5-Chloro-2-methoxyphenyl)-2,4-dihydro-5-[3-(trifluoromethyl)phenyl]-1,2,4-(3H)-triazol-3-one

(XXVIII¹³⁷: R₁=CF₃, R₂=R₃=R₄=H)

mp 240-243° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂: C, 51.98 H, 3.00; N,11,37. Found: C, 51.89; H, 3.02; N, 11.43.

EXAMPLE 1382-(5-Chloro-2-methoxyphenyl)-2,4-dihydro-5-[3,5-bis(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹³⁸: R₁=R₃=CF₃, R₂=R₄=H)

mp 227-230° C.; Anal. calcd. for C₁₇H₁₀ClF₆N₃O₂: C, 46.65 H, 2.30; N,9.60. Found: C, 46.82; H, 2.23; N, 9.55.

EXAMPLE 1395-[5-Chloro-2-methoxyphenyl]-2,4-dihydro-2-[4-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXIX¹³⁹)

mp 265.5-267.5° C.; Anal. calcd. for C₁₆H₁₁ClF₃N₃O₂: C, 51.97; H, 3.00;N, 11,37. Found: C, 51.90; H, 2.96; N, 11.43.

The following phenols were prepared according to the BBr₃ method ofExample 78.

EXAMPLES 140-145

EXAMPLE 1402-(5-Chloro-2-hydroxyphenyl)-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹⁴⁰: R₁=R₃=R₄=H, R₂=CF₃)

mp 252-255° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₂.0.1 H₂O: C, 50.40; H,2.59; N, 11.75. Found: C, 50.39; H, 2,46; N, 11.63.

EXAMPLE 1412-(5-Chloro-2-hydroxyphenyl)-2,4-dihydro-5-[3-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹⁴¹: R₁=CF₃, R₂=R₃=R₄=H)

mp 240-245° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₂: C, 50.65; H, 2.55; N,11.81. Found: C, 50.21; H, 2.50; N, 11.62.

EXAMPLE 1422-(5-Chloro-2-hydroxyphenyl)-2,4-dihydro-5-[2-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹⁴²: R₄=CF₃, R₁=R₂=R₃=H)

mp 167-170° C.; Anal. calcd. for C₁₅H₉ClF₃N₃O₂.0.78H₂O: C, 48.72; H,2.87; N, 11,36. Found: C, 48.73; H, 2.51; N, 11,32.

EXAMPLE 1432-(5-Chloro-2-hydroxyphenyl)-2,4-dihydro-5-[3,5-bis(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹⁴³: R₁=R₃=CF₃, R₂=R₄=H)

mp 250-253° C.; Anal. calcd. for C₁₆H₈ClF₆N₃O₂.0.5H₂O: C, 44.41; H,2.10; N, 9.71. Found: C, 44.62; H, 2.04; N, 9.61.

EXAMPLE 1442-(5-Chloro-2-hydroxyphenyl)-2,4-dihydro-5-[2,4-bis(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹⁴⁴: R₁=R₃=H, R₂=R₄=CF₃)

mp 270-275° C.; Anal. calcd. for C₁₆H₈ClF₆N₃O₂.1 H₂O.0.25 CH₂Cl₂: C,42.16; H, 2.28; N, 9.08. Found: C, 41.82; H, 2.18; N, 8.91.

EXAMPLE 1452-(5-Chloro-2-hydroxyphenyl)-2,4-dihydro-5-[3-chloro-4-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXVIII¹⁴⁵: R₁=Cl, R₂=CF₃, R₃=R₄=H)

mp 220-224° C.; Anal. calcd. for C₁₅H₈Cl₂F₃N₃O₂: C, 46.18; H, 2.07; N,10.77. Found: C, 45.99; H, 2.07; N, 10.54.

EXAMPLE 1465-[5-Chloro-2-hydroxyphenyl]-2,4-dihydro-2-[4-(trifluoromethyl)phenyl]-1,2,4(3H)-triazol-3-one

(XXIX¹⁴⁶)

mp >305° C.; Anal. calcd. for C₁₅H₉ClF₆N₃O₂: C, 50.65; H, 2.55; N,11.81. Found: C, 50.66; H, 2.67; N, 11.73.

Reasonable variations, such as those which would occur to a skilledartisan, can be made herein without departing from the scope of theinvention.

We claim:
 1. A compound of the Formula (1)

wherein “Het” is a moiety selected from the group consisting of(B),(D),(E) and (H)

wherein Z is independently for each occurrence selected from O or S;R^(a), R^(b) and R^(c) each are independently selected from hydrogen,halogen, OH, CF₃, NO₂, or

provided R^(c) is not hydrogen; and when R^(a) and R^(b) are hydrogen,R^(c) may be a heterocyclic moiety selected from the group consisting ofimidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, andpyridin-2-yl; R^(d) and R^(e) each are independently selected fromhydrogen, halogen, CF₃, NO₂ or imidazol-1-yl; m,n and p each areindependently selected from an integer of0 or 1; and R^(f) and R^(g)each are independently hydrogen; C₁₋₄ alkyl; or R^(f) and R^(g), takentogether with the nitrogen atom to which they are attached, is aheterocyclic moiety selected from the group consisting ofN-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine andimidazolinone; or a nontoxic pharmaceutically acceptable salt or solvatethereof.
 2. A compound of claim 1 in which “Het” is an imidazole moeityof group (D) or (E), and m=n=0.
 3. A compound of claim 2 selected fromthe group consisting of:4-Chloro-2-[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl]phenol;4-Chloro-2-[1-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]phenol;4-Chloro-2-[1-phenyl-1H-imidazol-2-yl]phenol; and1-(5-chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazole.4. The compound of claim 1 which is1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-5-phenyl-2H-imidazol-2-one. 5.A pharmaceutical composition for the treatment of disorders responsiveto openers of the large conductance calcium-activated potassium channelscomprising a therapeutically effective amount of a compound as definedin claim 1 in association with a pharmaceutically acceptable carrier ordiluent.
 6. A method for the treatment of disorders responsive toopening of the large conductance calcium-activated potassium channels ina mammal in need thereof, which comprises administering to said mammal atherapeutically effective amount of a compound as defined in claim
 1. 7.A method of claim 6 wherein said disorder is ischemia, convulsions,asthma, irritable bowel syndrome, migraine, traumatic brain injury, maleerectile dysfunction and urinary incontinence.
 8. The method of claim 7wherein the disorder is cerebral ischemia.